WO2010047120A1 - PYRIDINE DERIVATIVE HAVING SUBSTITUTED HETERO RING AND SUBSTITUTED γ-GLUTAMYLAMINO GROUP, AND ANTI-FUNGAL AGENT COMPRISING SAME - Google Patents
PYRIDINE DERIVATIVE HAVING SUBSTITUTED HETERO RING AND SUBSTITUTED γ-GLUTAMYLAMINO GROUP, AND ANTI-FUNGAL AGENT COMPRISING SAME Download PDFInfo
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- WO2010047120A1 WO2010047120A1 PCT/JP2009/005559 JP2009005559W WO2010047120A1 WO 2010047120 A1 WO2010047120 A1 WO 2010047120A1 JP 2009005559 W JP2009005559 W JP 2009005559W WO 2010047120 A1 WO2010047120 A1 WO 2010047120A1
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- OAAREAPNUNKZOP-UHFFFAOYSA-N CC(C)(C)C(NC1=NC=CCC1C(C)=O)=O Chemical compound CC(C)(C)C(NC1=NC=CCC1C(C)=O)=O OAAREAPNUNKZOP-UHFFFAOYSA-N 0.000 description 1
- JGNVFVXVKCTTOM-UHFFFAOYSA-N CC(C)(C)OC(N(c1ncccc1C(O1)=C)C1=O)=O Chemical compound CC(C)(C)OC(N(c1ncccc1C(O1)=C)C1=O)=O JGNVFVXVKCTTOM-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N CC(C)(C)OC(N)=O Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- OLGOTNLCPQXGLS-UHFFFAOYSA-N CC[n]1ncc(C)c1 Chemical compound CC[n]1ncc(C)c1 OLGOTNLCPQXGLS-UHFFFAOYSA-N 0.000 description 1
- KFCUYYYSICVTLH-UHFFFAOYSA-N CCc(cn1)c[n]1S Chemical compound CCc(cn1)c[n]1S KFCUYYYSICVTLH-UHFFFAOYSA-N 0.000 description 1
- UJGITZCPMNZJMH-UHFFFAOYSA-N CCc1c[n](C)nc1 Chemical compound CCc1c[n](C)nc1 UJGITZCPMNZJMH-UHFFFAOYSA-N 0.000 description 1
- UXRYUEYIWUWQIH-UHFFFAOYSA-N CCc1cc(C)n[o]1 Chemical compound CCc1cc(C)n[o]1 UXRYUEYIWUWQIH-UHFFFAOYSA-N 0.000 description 1
- LBETWQFXCZVMFP-UHFFFAOYSA-N CCc1n[o]c(C)c1 Chemical compound CCc1n[o]c(C)c1 LBETWQFXCZVMFP-UHFFFAOYSA-N 0.000 description 1
- WSEKTEUGRLFBSE-UHFFFAOYSA-O Nc1[nH+]cccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)n[o]1 Chemical compound Nc1[nH+]cccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)n[o]1 WSEKTEUGRLFBSE-UHFFFAOYSA-O 0.000 description 1
- KWLAZEIDKTZKBR-UHFFFAOYSA-N Nc1ncccc1-c1cc(CO)n[o]1 Chemical compound Nc1ncccc1-c1cc(CO)n[o]1 KWLAZEIDKTZKBR-UHFFFAOYSA-N 0.000 description 1
- FZFKOSQKPFVYOW-LGMDPLHJSA-N O/N=C(/Cc1ccc(COc2ncccc2)cc1)\Cl Chemical compound O/N=C(/Cc1ccc(COc2ncccc2)cc1)\Cl FZFKOSQKPFVYOW-LGMDPLHJSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- R 1 is a hydrogen atom, halogen atom, amino group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, hydroxy C 1-6 alkylamino group or C 1-6 alkoxy C 1-6 alkyl group means a hydrogen atom, an amino group, or a C 1-6 alkoxy C 1-6 alkyl group, and the C 1-6 alkoxy C 1-6 alkyl group is preferably a methoxymethyl group Is preferred.
- R is preferably a hydrogen atom, a methyl group, an ethyl group, or a 2-dimethylaminoethyl group.
- Z represents a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, -CH 2 O -, - OCH 2 -, - NH -, - NHCH 2 -, - CH 2 NH -, - CH 2 S-, Or —SCH 2 —, among which a methylene group, an oxygen atom, —CH 2 O—, or —OCH 2 — is preferable, and an oxygen atom, —CH 2 O—, or —OCH 2 — is particularly preferable.
- the compounds according to the present invention are adjusted to pH adjusters, solubilizers, tonicity agents, etc., and if necessary, solubilizers, stabilizers, etc. And is formulated by a conventional method.
- the method for producing the external preparation is not limited and can be produced by a conventional method. That is, as a base material used for formulation, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics, and the like can be used. Specific examples of the base material to be used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, and polyhydric alcohols.
- the form is not particularly limited, and it may be administered orally or parenterally by a commonly used method.
- tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, tapes, eye drops, nasal drops, ear drops, poultices It can be formulated and administered as an agent such as a lotion.
- the suspension was filtered using a filter and washed with a mixed solution of n-heptane / ethanol (n-heptane (70 kg) / ethanol (10 kg)) and then n-heptane (80 kg). After drying with nitrogen for 15 minutes or more, the wet solid was taken out into a SUS container. The wet solid was dried under reduced pressure in a shelf dryer under hot water circulation at 45 to 50 ° C. to obtain the title compound (54.55 kg, yield: 58.6%).
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- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Description
[1]下式(I)で表される化合物又はその塩;
R1が、水素原子、ハロゲン原子、アミノ基、R11-NH-(R11が、C1-6アルキル基、ヒドロキシC1-6アルキル基、C1-6アルコキシC1-6アルキル基、又はC1-6アルコキシカルボニルC1-6アルキル基を意味する。)、R12-(CO)-NH-(R12が、C1-6アルキル基又はC1-6アルコキシC1-6アルキル基)、C1-6アルキル基、ヒドロキシC1-6アルキル基、シアノC1-6アルキル基、C1-6アルコキシ基、又はC1-6アルコキシC1-6アルキル基を意味し;
R2が式
X及びYの一方が、窒素原子を、他方が、窒素原子又は酸素原子を意味し;
環Aが、ハロゲン原子若しくはC1-6アルキル基を1個若しくは2個有していてもよい、5若しくは6員のへテロアリール環又はベンゼン環を意味し;
Zが、単結合、メチレン基、エチレン基、酸素原子、硫黄原子、-CH2O-、-OCH2-、-NH-、-CH2NH-、-NHCH2-、-CH2S-、又は-SCH2-を意味し;
R3が、水素原子、ハロゲン原子、又は、それぞれ置換基群αから選ばれる置換基を1個若しくは2個有していてもよい、C1-6アルキル基、C3-8シクロアルキル基、C6-10アリール基、5若しくは6員へテロアリール基、又は5若しくは6員の非芳香族系へテロ環式基を意味し;
R4が、水素原子又はハロゲン原子を意味し;
Rが、水素原子、又はジメチルアミノ基で置換されていてもよいC1-6アルキル基を意味する。
[置換基群α]
ハロゲン原子、シアノ基、C1-6アルキル基、C1-6アルコキシ基、C1-6アルコキシカルボニル基、C3-8シクロアルキル基、C2-6アルケニル基、及びC2-6アルキニル基。
[2]
[4]
[5] X及びYがともに窒素原子である前項[1]に記載の化合物又はその塩。
[6]
[7] Rが水素原子、メチル基、エチル基、又は2-ジメチルアミノエチル基である前項[1]ないし[6]のいずれか1項に記載の化合物又はその塩。
[8] R1が、水素原子、アミノ基、又はC1-6アルコキシC1-6アルキル基である前項[7]に記載の化合物又はその塩。
[9] R1がアミノ基であって、Rが水素原子、メチル基、エチル基、又は2-ジメチルアミノエチル基である前項[1]ないし[6]のいずれか1項に記載の化合物又はその塩。
[10]R1がアミノ基であって、Rがメチル基、エチル基、又は2-ジメチルアミノエチル基である前項[1]ないし[6]のいずれか1項に記載の化合物又はその塩。
[11] 環Aが、ピリジン環、ベンゼン環、フラン環、チオフェン環、又はピロール環である前項[1]ないし[10]のいずれか1項に記載の化合物又はその塩。
[12] 環Aが、ピリジン環又はベンゼン環である前項[11]に記載の化合物又はその塩。
[13] Zが、酸素原子、-CH2O-、又は-OCH2-である前項[1]ないし[12]のいずれか1項に記載の化合物又はその塩。
[14] 前項[1]ないし[13]のいずれか1項に記載の化合物又はその塩を含有する医薬組成物。
[15] 前項[1]ないし[13]のいずれか1項に記載の化合物又はその塩を含有する医薬。
[16] 前項[1]ないし[13]のいずれか1項に記載の化合物又はその塩を有効成分とする抗真菌剤。
[17] 前項[1]ないし[13]のいずれか1項に記載の化合物又はその塩の薬理学的有効量を投与して、真菌感染症を予防及び/又は治療する方法。
[18] 抗真菌剤の製造のための前項[1]ないし[13]のいずれか1項に記載の化合物又はその塩の使用。
を提供する。 That is, the present invention
[1] A compound represented by the following formula (I) or a salt thereof;
R 1 is a hydrogen atom, a halogen atom, an amino group, R 11 —NH— (R 11 is a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, Or a C 1-6 alkoxycarbonyl C 1-6 alkyl group), R 12 — (CO) —NH— (wherein R 12 represents a C 1-6 alkyl group or a C 1-6 alkoxy C 1-6 alkyl group). Group), a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, a C 1-6 alkoxy group, or a C 1-6 alkoxy C 1-6 alkyl group;
R 2 is the formula
One of X and Y means a nitrogen atom, and the other means a nitrogen atom or an oxygen atom;
Ring A represents a 5- or 6-membered heteroaryl ring or benzene ring optionally having one or two halogen atoms or C 1-6 alkyl groups;
Z is a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, -CH 2 O -, - OCH 2 -, - NH -, -
R 3 may have a hydrogen atom, a halogen atom, or one or two substituents each selected from substituent group α, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, Means a C 6-10 aryl group, a 5 or 6 membered heteroaryl group, or a 5 or 6 membered non-aromatic heterocyclic group;
R 4 represents a hydrogen atom or a halogen atom;
R represents a hydrogen atom or a C 1-6 alkyl group which may be substituted with a dimethylamino group.
[Substituent group α]
Halogen atom, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkoxycarbonyl group, C 3-8 cycloalkyl group, C 2-6 alkenyl group, and C 2-6 alkynyl group .
[2]
[4]
[5] The compound or salt thereof according to [1], wherein X and Y are both nitrogen atoms.
[6]
[7] The compound or a salt thereof according to any one of [1] to [6], wherein R is a hydrogen atom, a methyl group, an ethyl group, or a 2-dimethylaminoethyl group.
[8] The compound or salt thereof according to [7] above, wherein R 1 is a hydrogen atom, an amino group, or a C 1-6 alkoxy C 1-6 alkyl group.
[9] The compound according to any one of [1] to [6], wherein R 1 is an amino group, and R is a hydrogen atom, a methyl group, an ethyl group, or a 2-dimethylaminoethyl group; Its salt.
[10] The compound or salt thereof according to any one of [1] to [6], wherein R 1 is an amino group, and R is a methyl group, an ethyl group, or a 2-dimethylaminoethyl group.
[11] The compound or salt thereof according to any one of [1] to [10], wherein Ring A is a pyridine ring, a benzene ring, a furan ring, a thiophene ring, or a pyrrole ring.
[12] The compound or salt thereof according to [11], wherein ring A is a pyridine ring or a benzene ring.
[13] The compound or the salt thereof according to any one of [1] to [12], wherein Z is an oxygen atom, —CH 2 O—, or —OCH 2 —.
[14] A pharmaceutical composition comprising the compound or salt thereof according to any one of [1] to [13].
[15] A medicament comprising the compound or salt thereof according to any one of [1] to [13].
[16] An antifungal agent comprising the compound according to any one of [1] to [13] or a salt thereof as an active ingredient.
[17] A method for preventing and / or treating a fungal infection by administering a pharmacologically effective amount of the compound or salt thereof according to any one of [1] to [13].
[18] Use of the compound according to any one of [1] to [13] or a salt thereof for the manufacture of an antifungal agent.
I will provide a.
[置換基群α]
ハロゲン原子、シアノ基、C1-6アルキル基、C1-6アルコキシ基、C1-6アルコキシカルボニル基、C3-8シクロアルキル基、C2-6アルケニル基、及びC2-6アルキニル基 R 3 is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group, a C 3-8 cycloalkyl group, each optionally having one or two substituents selected from substituent group α, A C 6-10 aryl group, or a 5- or 6-membered heteroaryl group.
[Substituent group α]
Halogen atom, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkoxycarbonyl group, C 3-8 cycloalkyl group, C 2-6 alkenyl group, and C 2-6 alkynyl group
式(I)で表される化合物(以下、化合物(I)という。)の製造方法について説明する。 [General manufacturing method]
A method for producing a compound represented by formula (I) (hereinafter referred to as compound (I)) will be described.
本工程は、化合物(1-1-1)を縮合剤の存在下で化合物(1-1-2)と反応させて化合物(1-1-3)を得る工程である。
本反応に用いる溶媒としては、出発原料をある程度溶解するものであり、かつ、反応を阻害しないものであれば、特に制限はないが、例えば、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、テトラヒドロフラン、1,4-ジオキサンなどのエーテル系溶媒、N,N-ジメチルホルムアミド、N-メチルピロリジノンなどのアミド系溶媒、ジメチルスルホキシドなどのスルホキシド系溶媒、酢酸エチルなどのエステル系溶媒、アセトニトリル、又はこれらの混合溶媒などを用いることができる。縮合剤としては、Bop(1H-1,2,3-ベンゾトリアゾール-1-イルオキシ(トリ(ジメチルアミノ))ホスホニウム ヘキサフルオロホスフェート)、HATU(O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロホスフェート)、WSC(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド・塩酸塩)、DCC(N,N-ジシクロヘキシルカルボジイミド)などを用いることができる。反応を促進するために、触媒量の4-ジメチルアミノピリジンを加えることもできる。また、本工程は、トリエチルアミンやN-メチルモルホリンなどの塩基を1当量から3当量加えて行うこともできる。化合物(1-1-2)は化合物(1-1-1)に対して1当量から溶媒量用いることができ、好ましくは溶媒量用いる。縮合剤は化合物(1-1-1)に対して1当量から3当量用いることができ、好ましくは1当量から1.5当量用いる。反応温度は0℃から還流温度であり、反応時間は10分間から48時間である。 [Step 1-1]
This step is a step of obtaining compound (1-1-3) by reacting compound (1-1-1) with compound (1-1-2) in the presence of a condensing agent.
The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, halogenated hydrocarbon solvents such as methylene chloride and chloroform, Ether solvents such as tetrahydrofuran and 1,4-dioxane, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, sulfoxide solvents such as dimethyl sulfoxide, ester solvents such as ethyl acetate, acetonitrile, or these A mixed solvent or the like can be used. As the condensing agent, Bop (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate), HATU (O- (7-azabenzotriazol-1-yl)- N, N, N ′, N′-tetramethyluronium hexafluorophosphate), WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride), DCC (N, N-dicyclohexylcarbodiimide), etc. Can be used. A catalytic amount of 4-dimethylaminopyridine can also be added to accelerate the reaction. This step can also be performed by adding 1 to 3 equivalents of a base such as triethylamine or N-methylmorpholine. Compound (1-1-2) can be used in the amount of 1 equivalent to a solvent amount based on compound (1-1-1), preferably the solvent amount is used. The condensing agent can be used in the amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (1-1-1). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 48 hours.
本工程は、化合物(1-1-3)を、水素雰囲気下でパラジウム触媒を用いてベンジル基を脱保護し、得られたカルボン酸と化合物(1-1)を縮合剤の存在下で反応させて化合物(1-2)を得る工程である。ベンジル基の脱保護の反応に用いる溶媒としては、出発原料をある程度溶解するものであり、かつ、反応を阻害しないものであれば、特に制限はないが、例えば、テトラヒドロフラン、1,4-ジオキサンなどのエーテル系溶媒、メタノール、エタノールなどのアルコール系溶媒、酢酸エチルなどのエステル系溶媒、又はこれらの混合溶媒などを用いることができる。パラジウム触媒としてはパラジウム-カーボン、水酸化パラジウムなどを用いることができる。縮合反応に用いる溶媒としては、出発原料をある程度溶解するものであり、かつ、反応を阻害しないものであれば、特に制限はないが、例えば、塩化メチレン、クロロホルム等のハロゲン化炭化水素系溶媒、テトラヒドロフラン、1,4-ジオキサンなどのエーテル系溶媒、N,N-ジメチルホルムアミド、N-メチルピロリジノンなどのアミド系溶媒、ジメチルスルホキシドなどのスルホキシド系溶媒、酢酸エチルなどのエステル系溶媒、アセトニトリル、又はこれらの混合溶媒などを用いることができる。縮合剤としては、Bop(1H-1,2,3-ベンゾトリアゾール-1-イルオキシ(トリ(ジメチルアミノ))ホスホニウム ヘキサフルオロホスフェート)、HATU(O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロホスフェート)、WSC(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド・塩酸塩)、DCC(N,N-ジシクロヘキシルカルボジイミド)などを用いることができる。反応を促進するために、触媒量の4-ジメチルアミノピリジンを加えることもできる。また、本工程は、トリエチルアミンやN-メチルモルホリンなどの塩基を1当量から3当量加えて行うこともできる。化合物(1-1-3)は化合物(1-1)に対して1当量から3当量用いることができる。パラジウム触媒は化合物(1-1)に対して0.01当量から1当量用いることができる。縮合剤は化合物(1-1)に対して1当量から3当量用いることができる。反応温度は0℃から還流温度であり、反応時間は10分間から48時間である。 [Step 1-2]
In this step, compound (1-1-3) is deprotected using a palladium catalyst in a hydrogen atmosphere, and the resulting carboxylic acid and compound (1-1) are reacted in the presence of a condensing agent. In this step, compound (1-2) is obtained. The solvent used for the deprotection reaction of the benzyl group is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, tetrahydrofuran, 1,4-dioxane, etc. Ether solvents, alcohol solvents such as methanol and ethanol, ester solvents such as ethyl acetate, or a mixed solvent thereof can be used. As the palladium catalyst, palladium-carbon, palladium hydroxide, or the like can be used. The solvent used in the condensation reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, halogenated hydrocarbon solvents such as methylene chloride and chloroform, Ether solvents such as tetrahydrofuran and 1,4-dioxane, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, sulfoxide solvents such as dimethyl sulfoxide, ester solvents such as ethyl acetate, acetonitrile, or these A mixed solvent or the like can be used. As the condensing agent, Bop (1H-1,2,3-benzotriazol-1-yloxy (tri (dimethylamino)) phosphonium hexafluorophosphate), HATU (O- (7-azabenzotriazol-1-yl)- N, N, N ′, N′-tetramethyluronium hexafluorophosphate), WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride), DCC (N, N-dicyclohexylcarbodiimide), etc. Can be used. A catalytic amount of 4-dimethylaminopyridine can also be added to accelerate the reaction. This step can also be performed by adding 1 to 3 equivalents of a base such as triethylamine or N-methylmorpholine. Compound (1-1-3) can be used in the amount of 1 to 3 equivalents based on compound (1-1). The palladium catalyst can be used in the amount of 0.01 to 1 equivalent based on compound (1-1). The condensing agent can be used in the amount of 1 to 3 equivalents based on compound (1-1). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 48 hours.
本工程は、化合物(1-2)のt-ブトキシカルボニル基を酸性条件下で脱保護して化合物(I)を得る工程である。本反応に用いる溶媒としては、出発原料をある程度溶解するものであり、かつ、反応を阻害しないものであれば、特に制限はないが、例えば、1,4-ジオキサン、テトラヒドロフランなどのエーテル系溶媒、ベンゼン、トルエン、などの芳香族炭化水素系溶媒、メタノール、エタノールなどのアルコール系溶媒、塩化メチレン、水、又はこれらの混合溶媒などを用いることができる。酸としては塩酸、硫酸、臭化水素酸、トリフルオロ酢酸、ギ酸などを用いることができる。酸は化合物(1-2)に対して2当量から溶媒量用いる。反応温度は0℃から還流温度であり、反応時間は10分間から24時間である。 [Step 1-3]
This step is a step of obtaining compound (I) by deprotecting the t-butoxycarbonyl group of compound (1-2) under acidic conditions. The solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction. For example, ether solvents such as 1,4-dioxane and tetrahydrofuran, Aromatic hydrocarbon solvents such as benzene and toluene, alcohol solvents such as methanol and ethanol, methylene chloride, water, or a mixed solvent thereof can be used. As the acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, formic acid and the like can be used. The acid is used in the amount of 2 equivalents to a solvent amount based on compound (1-2). The reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
本工程は、化合物(1-1)を縮合剤の存在下でN-t-ブトキシカルボニル-L-グルタミック アシッド 1-t-ブチルエステルと反応させて化合物(2-1)を得る工程である。[工程1-1]と同様の方法で化合物(2-1)を製造することができる。 [Step 2-1]
In this step, compound (1-1) is reacted with Nt-butoxycarbonyl-L-glutamic acid 1-t-butyl ester in the presence of a condensing agent to obtain compound (2-1). Compound (2-1) can be produced by the same method as in [Step 1-1].
本工程は、化合物(2-1)の2つのt-ブトキシカルボニル基を酸性条件下で脱保護して化合物(Ia)を得る工程である。[工程1-3]と同様の方法で化合物(Ia)を製造することができる。 [Step 2-2]
This step is a step of obtaining compound (Ia) by deprotecting two t-butoxycarbonyl groups of compound (2-1) under acidic conditions. Compound (Ia) can be produced in the same manner as in [Step 1-3].
1H-NMR Spectrum (CDCl3)δ(ppm):4.08(2H,s), 5.37(2H,s), 6.33(1H,s), 6.45(2H,brs), 6.79-6.82(2H,m), 6.88-6.91(1H,m), 7.30(2H,d,J=8.1Hz), 7.45(2H,d,J=8.1Hz), 7.57-7.61(1H,m), 7.85(1H,d,J=7.3Hz), 8.03(1H,d,J=5.5Hz), 8.17(1H,m).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 4.08 (2H, s), 5.37 (2H, s), 6.33 (1H, s), 6.45 (2H, brs), 6.79-6.82 (2H, m) , 6.88-6.91 (1H, m), 7.30 (2H, d, J = 8.1Hz), 7.45 (2H, d, J = 8.1Hz), 7.57-7.61 (1H, m), 7.85 (1H, d, J = 7.3Hz), 8.03 (1H, d, J = 5.5Hz), 8.17 (1H, m).
1H-NMR Spectrum (CDCl3)δ(ppm):4.71(2H,s), 5.38(2H,s), 6.81(1H,td,J=0.9,8.4Hz), 6.89(1H,ddd,J=0.9,5.1,7.1Hz), 7.37-7.47(4H,m), 7.59(1H,ddd,J=2.0,7.1,8.3Hz), 8.17(1H,ddd,J=0.7,2.0,5.1Hz).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 4.71 (2H, s), 5.38 (2H, s), 6.81 (1H, td, J = 0.9,8.4Hz), 6.89 (1H, ddd, J = 0.9,5.1,7.1Hz), 7.37-7.47 (4H, m), 7.59 (1H, ddd, J = 2.0,7.1,8.3Hz), 8.17 (1H, ddd, J = 0.7,2.0,5.1Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):5.48(2H,s), 6.85(1H,d,J=8.2Hz), 6.90-6.93(1H,m), 7.60-7.64(3H,m), 7.89(2H,d,J=8.1Hz), 8.16(1H,dd,J=1.3,4.9Hz), 10.0(1H,s).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 5.48 (2H, s), 6.85 (1H, d, J = 8.2Hz), 6.90-6.93 (1H, m), 7.60-7.64 (3H, m) , 7.89 (2H, d, J = 8.1Hz), 8.16 (1H, dd, J = 1.3,4.9Hz), 10.0 (1H, s).
1H-NMR Spectrum (DMSO-d6)δ(ppm):5.41(2H,s), 6.91(1H,dd,J=0.8,8.4Hz), 6.99-7.10(1H,m), 7.53(2H,d,J=8.0Hz), 7.72-7.79(1H,m), 7.86(2H,d,J=8.0Hz), 8.13(1H,d,J=10Hz), 8.15-8.20(1H,m), 8.23(1H,d,J=10Hz).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 5.41 (2H, s), 6.91 (1H, dd, J = 0.8, 8.4Hz), 6.99-7.10 (1H, m), 7.53 (2H, d, J = 8.0Hz), 7.72-7.79 (1H, m), 7.86 (2H, d, J = 8.0Hz), 8.13 (1H, d, J = 10Hz), 8.15-8.20 (1H, m), 8.23 (1H, d, J = 10Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):3.23(2H,t,J=6.8Hz), 4.85(2H,t,J=6.8Hz), 5.32(2H,s) 6.82-6.88(1H,m), 6.96-7.01(1H,m), 7.28(2H,d,J=8.0Hz), 7.38(2H,d,J=8.0Hz), 7.69-7.74(1H,m), 8.15-8.19(1H,m).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 3.23 (2H, t, J = 6.8Hz), 4.85 (2H, t, J = 6.8Hz), 5.32 (2H, s) 6.82-6.88 ( 1H, m), 6.96-7.01 (1H, m), 7.28 (2H, d, J = 8.0Hz), 7.38 (2H, d, J = 8.0Hz), 7.69-7.74 (1H, m), 8.15-8.19 (1H, m).
1H-NMR Spectrum (DMSO-d6)δ(ppm):3.82(2H,s), 5.33(2H,s), 6.84-6.89(1H,m), 6.97-7.01(1H,m), 7.25(2H,d,J=8.4Hz), 7.41(2H,d,J=8.4Hz), 7.70-7.76(1H,m), 8.15-8.18(1H,m), 11.7(1H,s).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 3.82 (2H, s), 5.33 (2H, s), 6.84-6.89 (1H, m), 6.97-7.01 (1H, m), 7.25 ( 2H, d, J = 8.4Hz), 7.41 (2H, d, J = 8.4Hz), 7.70-7.76 (1H, m), 8.15-8.18 (1H, m), 11.7 (1H, s).
1H-NMR Spectrum (CDCl3)δ(ppm):5.33(2H,s), 6.87-6.70(1H,m), 6.98-7.02(1H,m) 7.38-7.44(2H,m), 7.55-7.60(2H,m), 7.71-7.76(1H,m), 8.15-8.18(1H,m).
1 H-NMR Spectrum (CDCl3) δ (ppm): 5.33 (2H, s), 6.87-6.70 (1H, m), 6.98-7.02 (1H, m) 7.38-7.44 (2H, m), 7.55-7.60 ( 2H, m), 7.71-7.76 (1H, m), 8.15-8.18 (1H, m).
1H-NMR Spectrum (CDCl3)δ(ppm):4.07(2H,s), 5.37(4H,brs), 6.25(1H,s), 6.71(1H,dd,J=4.8,7.7Hz), 6.79-6.81(1H,m), 6.89(1H,ddd,J=0.8,5.0,7.0Hz), 7.30(2H,d,J=7.9Hz), 7.44(2H,d,J=8.1Hz), 7.58(1H,ddd,J=2.0,7.1,8.4Hz), 7.70(1H,dd,J=1.8,7.7Hz), 8.14(1H,dd,J=1.8,4.9Hz), 8.17-8.18(1H,m).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 4.07 (2H, s), 5.37 (4H, brs), 6.25 (1H, s), 6.71 (1H, dd, J = 4.8, 7.7 Hz), 6.79 -6.81 (1H, m), 6.89 (1H, ddd, J = 0.8,5.0,7.0Hz), 7.30 (2H, d, J = 7.9Hz), 7.44 (2H, d, J = 8.1Hz), 7.58 ( 1H, ddd, J = 2.0,7.1,8.4Hz), 7.70 (1H, dd, J = 1.8,7.7Hz), 8.14 (1H, dd, J = 1.8,4.9Hz), 8.17-8.18 (1H, m) .
1H-NMR Spectrum (CDCl3)δ(ppm):3.51(1H,d,J=1.8Hz), 3.83(3H,s), 4.11(1H,d,J=1.8Hz), 5.38(2H,s), 6.81(1H,td,J=0.9,8.4Hz), 6.89(1H,ddd,J=0.9,5.1,7.1Hz), 7.29-7.31(2H,m), 7.47(2H,d,J=8.2Hz), 7.59(1H,ddd,J=2.0,7.1,8.4Hz), 8.17(1H,ddd,J=0.8,2.0,5.1Hz).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 3.51 (1H, d, J = 1.8Hz), 3.83 (3H, s), 4.11 (1H, d, J = 1.8Hz), 5.38 (2H, s ), 6.81 (1H, td, J = 0.9,8.4Hz), 6.89 (1H, ddd, J = 0.9,5.1,7.1Hz), 7.29-7.31 (2H, m), 7.47 (2H, d, J = 8.2 Hz), 7.59 (1H, ddd, J = 2.0, 7.1, 8.4 Hz), 8.17 (1 H, ddd, J = 0.8, 2.0, 5.1 Hz).
1H-NMR Spectrum (CD3OD)δ(ppm):3.31(1H,d,J=1.8Hz), 3.88(1H,d,J=1.8Hz), 5.33(2H,s), 6.84(1H,td,J=0.9,8.2Hz), 6.94(1H,ddd,J=0.9,5.1,7.1Hz), 7.29-7.31(2H,m), 7.42(2H,d,J=8.2Hz), 7.68(1H,ddd,J=2.0,7.1,8.4Hz), 8.12(1H,ddd,J=0.7,2.0,5.1Hz).
1 H-NMR Spectrum (CD 3 OD) δ (ppm): 3.31 (1H, d, J = 1.8 Hz), 3.88 (1H, d, J = 1.8 Hz), 5.33 (2H, s), 6.84 (1H, td, J = 0.9,8.2Hz), 6.94 (1H, ddd, J = 0.9,5.1,7.1Hz), 7.29-7.31 (2H, m), 7.42 (2H, d, J = 8.2Hz), 7.68 (1H , ddd, J = 2.0,7.1,8.4Hz), 8.12 (1H, ddd, J = 0.7,2.0,5.1Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):3.70(2H,d,J=2.2Hz), 5.38(2H,s), 6.81(1H,td,J=0.8,8.2Hz), 6.89(1H,ddd,J=0.9,5.1,7.1Hz), 7.24(2H,d,J=8.1), 7.48(2H,d,J=8.1Hz), 7.59(1H,ddd,J=2.0,7.1,8.4Hz), 8.18(1H,ddd,J=0.6,2.0,5.0Hz), 9.75(1H,t,J=2.4).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 3.70 (2H, d, J = 2.2Hz), 5.38 (2H, s), 6.81 (1H, td, J = 0.8,8.2Hz), 6.89 (1H , ddd, J = 0.9,5.1,7.1Hz), 7.24 (2H, d, J = 8.1), 7.48 (2H, d, J = 8.1Hz), 7.59 (1H, ddd, J = 2.0,7.1,8.4Hz ), 8.18 (1H, ddd, J = 0.6,2.0,5.0Hz), 9.75 (1H, t, J = 2.4).
1H-NMR Spectrum (CDCl3)δ(ppm):3.54(2H,d,J=6.2Hz), 3.74(2H,d,J=5.3Hz), 5.36(2H+2H,s), 6.79-6.81(1H+1H,m), 6.87-6.90(1H+2H,m), 7.22-7.24(2H+2H,m), 7.42-7.44(2H+2H,m), 7.53(1H,t,J=6.3 Hz), 7.56-7.61(1H+1H,m), 8.17-8.18(1H+1H,m)(underbar=E or Z).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 3.54 ( 2H , d, J = 6.2Hz), 3.74 (2H, d, J = 5.3Hz), 5.36 ( 2H + 2H, s), 6.79-6.81 ( 1H + 1H, m), 6.87-6.90 ( 1H + 2H, m), 7.22-7.24 ( 2H + 2H, m), 7.42-7.44 ( 2H + 2H, m), 7.53 ( 1H , t, J = 6.3 Hz), 7.56-7.61 ( 1H + 1H, m), 8.17-8.18 ( 1H + 1H, m) (underbar = E or Z).
1H-NMR Spectrum (CDCl3)δ(ppm):3.81(2H,s), 5.36(2H,s), 6.81(1H,d,J=8.2Hz), 6.88-6.91 (1H,m), 7.28(2H,d,J=8.1), 7.43(2H,d,J=8.1Hz), 7.57-7.62(1H,m), 8.17-8.19(1H,m).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 3.81 (2H, s), 5.36 (2H, s), 6.81 (1H, d, J = 8.2 Hz), 6.88-6.91 (1H, m), 7.28 (2H, d, J = 8.1), 7.43 (2H, d, J = 8.1Hz), 7.57-7.62 (1H, m), 8.17-8.19 (1H, m).
1H-NMR Spectrum (DMSO-d6)δ(ppm):4.04(2H,s), 5.32(2H,s), 6.26(2H,brs), 6.69(1H,dd,J=4.8,8.0Hz), 6.81(1H,s), 6.83-6.87(1H,m), 6.97-7.00(1H,m), 7.33(2H,d,J=8.0Hz), 7.40(2H,d,J=8.0Hz), 7.69-7.74(1H,m), 7.87(1H,dd,J=2.0,7.6Hz), 8.08(1H,dd,J=2.0,7.6Hz), 8.15-8.17(1H,m).
1 H-NMR Spectrum (DMSO-d6) δ (ppm): 4.04 (2H, s), 5.32 (2H, s), 6.26 (2H, brs), 6.69 (1H, dd, J = 4.8, 8.0 Hz), 6.81 (1H, s), 6.83-6.87 (1H, m), 6.97-7.00 (1H, m), 7.33 (2H, d, J = 8.0Hz), 7.40 (2H, d, J = 8.0Hz), 7.69 -7.74 (1H, m), 7.87 (1H, dd, J = 2.0,7.6Hz), 8.08 (1H, dd, J = 2.0,7.6Hz), 8.15-8.17 (1H, m).
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.32(18H,s), 4.59(1H,s), 7.39-7.44(1H,m), 7.99-8.03(1H,m), 8.46-8.48(1H,m).
1 H-NMR Spectrum (DMSO-d6) δ (ppm): 1.32 (18H, s), 4.59 (1H, s), 7.39-7.44 (1H, m), 7.99-8.03 (1H, m), 8.46-8.48 (1H, m).
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.18(18H,s), 4.07(2H,s), 5.32(2H,s), 6.58(1H,s), 6.83-6.86(1H,m), 6.96-7.01(1H,m), 7.29(2H,d,J=8.0Hz), 7.40(2H,d,J=8.0Hz), 7.58(1H,dd,J=4.8,7.6Hz), 7.69-7.74(1H,m), 8.15-8.18(1H,m), 8.34(1H,dd,J=2.0,7.6Hz), 8.59(1H,dd,J=2.0,5.2Hz).
1 H-NMR Spectrum (DMSO-d6) δ (ppm): 1.18 (18H, s), 4.07 (2H, s), 5.32 (2H, s), 6.58 (1H, s), 6.83-6.86 (1H, m ), 6.96-7.01 (1H, m), 7.29 (2H, d, J = 8.0Hz), 7.40 (2H, d, J = 8.0Hz), 7.58 (1H, dd, J = 4.8,7.6Hz), 7.69 -7.74 (1H, m), 8.15-8.18 (1H, m), 8.34 (1H, dd, J = 2.0,7.6Hz), 8.59 (1H, dd, J = 2.0,5.2Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.18(18H,s), 4.07(2H,s), 5.32(2H,s), 6.58(1H,s), 6.83-6.86(1H,m), 6.96-7.01(1H,m), 7.29(2H,d,J=8.0Hz), 7.40(2H,d,J=8.0Hz), 7.58(1H,dd,J=4.8,7.6Hz), 7.69-7.74(1H,m), 8.15-8.18(1H,m), 8.34(1H,dd,J=2.0,7.6Hz), 8.59(1H,dd,J=2.0,5.2Hz).
1 H-NMR Spectrum (DMSO-d6) δ (ppm): 1.18 (18H, s), 4.07 (2H, s), 5.32 (2H, s), 6.58 (1H, s), 6.83-6.86 (1H, m ), 6.96-7.01 (1H, m), 7.29 (2H, d, J = 8.0Hz), 7.40 (2H, d, J = 8.0Hz), 7.58 (1H, dd, J = 4.8,7.6Hz), 7.69 -7.74 (1H, m), 8.15-8.18 (1H, m), 8.34 (1H, dd, J = 2.0,7.6Hz), 8.59 (1H, dd, J = 2.0,5.2Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.56(9H,s), 5.01(1H,d,J=3.6Hz), 5.45(1H,d,J=3.6Hz), 7.28(1H,dd,J=4.8,8.0Hz), 8.25(1H,dd,J=1.6,8.0Hz), 8.36(1H,dd,J=1.6,4.8Hz).
1 H-NMR Spectrum (DMSO-d6) δ (ppm): 1.56 (9H, s), 5.01 (1H, d, J = 3.6Hz), 5.45 (1H, d, J = 3.6Hz), 7.28 (1H, dd, J = 4.8,8.0Hz), 8.25 (1H, dd, J = 1.6,8.0Hz), 8.36 (1H, dd, J = 1.6,4.8Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.47(9H,s), 6.99-7.03(1H,m), 7.70-7.74(1H,m), 7.77-7.80(1H,m), 8.23-8.24(1H,m), 9.72(1H,brs).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 1.47 (9H, s), 6.99-7.03 (1H, m), 7.70-7.74 (1H, m), 7.77-7.80 (1H, m), 8.23-8.24 (1H, m), 9.72 (1H, brs).
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.32-1.41(9H,m), 6.80-6.84(1H,m), 7.95-7.8.13(2H,m).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 1.32—1.41 (9H, m), 6.80-6.84 (1H, m), 7.95—7.8.13 (2H, m).
1H-NMR Spectrum (DMSO-d6)δ(ppm):0.81-0.85(9H,m), 1.08-1.12(6H,m), 1.23-1.30(6H,m), 1.46-1.54(6H,m), 4.00(2H,s), 5.30(2H,s), 6.40(1H,s), 6.83-6.86(1H,m), 6.97-7.00(1H,m), 7.25-7.26(2H,m), 7.36-7.38(2H,m), 7.69-7.74(1H,m), 8.15-8.17(1H,m).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 0.81-0.85 (9H, m), 1.08-1.12 (6H, m), 1.23-1.30 (6H, m), 1.46-1.54 (6H, m ), 4.00 (2H, s), 5.30 (2H, s), 6.40 (1H, s), 6.83-6.86 (1H, m), 6.97-7.00 (1H, m), 7.25-7.26 (2H, m), 7.36-7.38 (2H, m), 7.69-7.74 (1H, m), 8.15-8.17 (1H, m).
1H-NMR Spectrum (DMSO-d6)δ(ppm):3.99(2H,s), 5.31(2H,s), 6.66(1H,s), 6.84-6.87(1H,m), 6.97-7.00(1H,m), 7.26(2H,d,J=8Hz), 7.39(2H,d,J=8Hz), 7.70-7.74(1H,m), 8.16-8.17(1H,m).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 3.99 (2H, s), 5.31 (2H, s), 6.66 (1H, s), 6.84-6.87 (1H, m), 6.97-7.00 ( 1H, m), 7.26 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.70-7.74 (1H, m), 8.16-8.17 (1H, m).
[参考例2]tert-ブチル (3-アセチルピリジン-2-イル)カルバメートの合成
1H-NMR Spectrum (CDCl3)δ(ppm):1.54(9H,s), 2.64(3H,s), 7.03(1H,dd,J=4.8,8.0Hz), 8.16(1H,dd,J=2.0,8.0Hz), 8.63(1H,dd,J=2.0,4.8Hz), 10.82(1H,brs). Hereinafter, another method for producing 3- (3- (4- (pyridin-2-yloxymethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine described in Reference Example 1 will be described. .
[Reference Example 2] Synthesis of tert-butyl (3-acetylpyridin-2-yl) carbamate
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.54 (9H, s), 2.64 (3H, s), 7.03 (1H, dd, J = 4.8, 8.0 Hz), 8.16 (1H, dd, J = 2.0, 8.0Hz), 8.63 (1H, dd, J = 2.0, 4.8Hz), 10.82 (1H, brs).
1H-NMR Spectrum (CDCl3)δ(ppm):1.45(3H,t,J=7.2Hz), 4.49(2H,q,J=7.2Hz), 5.40(2H,brs), 6.79(1H,dd,J=5.2,7.6Hz), 6.91(1H,s), 7.81(1H,dd,J=2.0,7.6Hz), 8.21(1H,dd,J=2.0,5.2Hz). [Reference Example 3] Synthesis of ethyl 5- (2-aminopyridin-3-yl) isoxazole-3-carboxylate
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.45 (3H, t, J = 7.2Hz), 4.49 (2H, q, J = 7.2Hz), 5.40 (2H, brs), 6.79 (1H, dd , J = 5.2, 7.6Hz), 6.91 (1H, s), 7.81 (1H, dd, J = 2.0, 7.6Hz), 8.21 (1H, dd, J = 2.0, 5.2Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):4.56(2H,d,J=5.6Hz), 5.54(1H,t,J=5.6Hz), 6.27(2H,brs), 6.72(1H,dd,J=4.8,7.6Hz), 6.90(1H,s), 7.90(1H,dd,J=2.0,7.6Hz), 8.10(1H,dd,J=2.0,4.8Hz). Reference Example 4 Synthesis of [5- (2-aminopyridin-3-yl) isoxazol-3-yl] methanol
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 4.56 (2H, d, J = 5.6Hz), 5.54 (1H, t, J = 5.6Hz), 6.27 (2H, brs), 6.72 (1H , dd, J = 4.8,7.6Hz), 6.90 (1H, s), 7.90 (1H, dd, J = 2.0,7.6Hz), 8.10 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.33(9H,s), 2.64(3H,s), 7.10(1H,dd,J=4.8,8.0Hz), 8.17(1H,dd,J=2.0,7.6Hz), 8.64(1H,dd,J=2.0,4.8Hz).
*2-tert-ブチル-4-メチル-4H-ピリド[2,3-d][1,3]オキサジン-4-イル ピバレート
1H-NMR Spectrum (CDCl3)δ(ppm):1.09(9H,s), 1.32(9H,s), 2.05(3H,s), 7.14(1H,dd,J=4.8,7.6Hz), 7.71(1H,dd,J=2.0,7.6Hz), 8.51(1H,dd,J=2.0,4.8Hz). [Reference Example 5] Synthesis of N- (3-acetylpyridin-2-yl) -2,2-dimethylpropanamide
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.33 (9H, s), 2.64 (3H, s), 7.10 (1H, dd, J = 4.8, 8.0 Hz), 8.17 (1H, dd, J = 2.0,7.6Hz), 8.64 (1H, dd, J = 2.0,4.8Hz).
* 2-tert-butyl-4-methyl-4H-pyrido [2,3-d] [1,3] oxazin-4-yl pivalate
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.09 (9H, s), 1.32 (9H, s), 2.05 (3H, s), 7.14 (1H, dd, J = 4.8, 7.6 Hz), 7.71 (1H, dd, J = 2.0,7.6Hz), 8.51 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.45(9H,s), 7.48(1H,dd,J=4.8,8.0Hz), 8.52(1H,dd,J=2.0,7.6Hz), 8.97(1H,dd,J=2.0,4.8Hz). [Reference Example 6] Synthesis of 2-tert-butyl-4H-pyrido [2,3-d] [1,3] oxazin-4-one
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.45 (9H, s), 7.48 (1H, dd, J = 4.8, 8.0 Hz), 8.52 (1H, dd, J = 2.0, 7.6 Hz), 8.97 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.33(9H,s), 2.64(3H,s), 7.10(1H,dd,J=4.8,8.0Hz), 8.17(1H,dd,J=2.0,7.6Hz), 8.64(1H,dd,J=2.0,4.8Hz). [Reference Example 7] Synthesis of N- (3-acetylpyridin-2-yl) -2,2-dimethylpropanamide
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.33 (9H, s), 2.64 (3H, s), 7.10 (1H, dd, J = 4.8, 8.0 Hz), 8.17 (1H, dd, J = 2.0, 7.6Hz), 8.64 (1H, dd, J = 2.0, 4.8Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.19(9H,s), 1.32(3H,t), 4.37(4H,q), 7.12(1H,s), 7.46(1H,dd,J=4.8,8.0Hz), 8.25(1H,dd,J=2.0,8.0Hz), 8.58(1H,dd,J=2.0,4.8Hz), 10.03(1H,s). [Reference Example 8] Synthesis of ethyl 5- {2-[(2,2-dimethylpropanoyl) amino] pyridin-3-yl} isoxazole-3-carboxylate
1 H-NMR Spectrum (DMSO-d6) δ (ppm): 1.19 (9H, s), 1.32 (3H, t), 4.37 (4H, q), 7.12 (1H, s), 7.46 (1H, dd, J = 4.8, 8.0 Hz), 8.25 (1 H, dd, J = 2.0, 8.0 Hz), 8.58 (1 H, dd, J = 2.0, 4.8 Hz), 10.03 (1 H, s).
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.20(9H,s), 4.52(2H,d,J=6.0Hz), 5.53(1H,t,J=6.0Hz), 6.70(1H,s), 7.44(1H,dd,J=4.8,8.0Hz), 8.19(1H,dd,J=5.6,7.6Hz), 8.53(1H,dd,J=2.0,4.8Hz), 9.89(1H,brs). [Reference Example 9] Synthesis of N- {3- [3- (hydroxymethyl) isoxazol-5-yl] pyridin-2-yl} -2,2 dimethylpropanamide
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 1.20 (9H, s), 4.52 (2H, d, J = 6.0Hz), 5.53 (1H, t, J = 6.0Hz), 6.70 (1H , s), 7.44 (1H, dd, J = 4.8,8.0Hz), 8.19 (1H, dd, J = 5.6,7.6Hz), 8.53 (1H, dd, J = 2.0,4.8Hz), 9.89 (1H, brs).
1H-NMR Spectrum (DMSO-d6)δ(ppm):4.54(2H,s), 5.57(1H,brs), 6.25(2H,brs), 6.71(1H,dd,J=4.8,8.0Hz), 6.90(1H,s), 7.90(1H,dd,J=1.6,7.6Hz), 8.09(1H,dd,J=1.6,4.8Hz). [Reference Example 10] Synthesis of [5- (2-aminopyridin-3-yl) isoxazol-3-yl] methanol
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 4.54 (2H, s), 5.57 (1H, brs), 6.25 (2H, brs), 6.71 (1H, dd, J = 4.8, 8.0 Hz) , 6.90 (1H, s), 7.90 (1H, dd, J = 1.6, 7.6Hz), 8.09 (1H, dd, J = 1.6, 4.8Hz).
ブライン冷却下、水(100L)を内温30℃以下で滴下し、続いて、35%塩酸(49.0kg,1.6M/M)を内温30℃以下で滴下した。反応溶液を5分間攪拌後、15分間以上静置し、下層(a)をポリ容器に取り分けた。水(100L)を加え、5分間攪拌した後、15分以上静置した。下層(c)をポリ容器に取り分け、上層(d)を取り出した後、下層(a)および下層(c)を1500L反応缶へ戻した。ブライン冷却下、酢酸エチル(289kg)を加え、続いて48.7%水酸化ナトリウム水溶液(43.4kg,1.8M/M)を内温30℃以下で滴下し、5分間攪拌後、下層のpHが8~9であることをUNIV試験紙にて確認した。15分以上静置した後、下層(e)、上層(f)をそれぞれ取り分け、下層(e)を1500L反応缶へ戻した。酢酸エチル(144kg)を加え、5分間攪拌後、15分間以上静置し、下層(g)、上層(h)をそれぞれ取り分けた。下層(g)を1500L反応缶へ戻して酢酸エチル(144kg)を加え、5分間攪拌後、15分以上静置した。下層(i)を取り出した後、上層(f)と上層(h)を1500L反応缶へ戻し、酢酸エチル(約15kg)で洗い込んだ。
1500L反応缶に戻した有機層を減圧濃縮し(温水50℃)、濃縮液が約200Lになった時点で濃縮を一旦終了した。濃縮液をSUS容器に取り出し、缶内をトルエン(17kg)で洗い出した。取り出した濃縮液の約半量を300L反応缶へ入れ,トルエン(9kg)で洗い込んだ。濃縮液をさらに減圧濃縮し(温水50℃)、コンデンサーからの留出量が減ったところで残りの濃縮液を300L反応缶へ入れ、トルエン(9kg)で洗い込んだ。減圧濃縮を再開した(温水50℃~70℃)。留出が殆んど無くなった時点で、水冷却を開始し、内温50℃以下でトルエン(52kg)を加えた。減圧濃縮を再開した(温水50~80℃)。外温80℃、減圧度-0.090MPa以上で留出を認めなくなった時点で濃縮を終了し、内温20~30℃でエタノール(61kg)を加えた。
窒素雰囲気下,缶内のエタノール溶液をSUS容器に取り出し、エタノール(13kg)で洗い出した。取り出した溶液を1500L反応缶へ加えた後、エタノール(13kg)で洗い込み、標記化合物のエタノール溶液(目的物を69.4kg含有,収率:107.3%)を得た。
HPLC条件 カラム:YMC-Pack Pro C18 (5μm, 150x4.6mmI.D., YMC),移動相:アセトニトリル/水/酢酸アンモニウム=300/700/1~900/100/1(v/v/w)。 [Reference Example 11] Synthesis of N- (3-acetylpyridin-2-yl) -2,2-dimethylpropanamide
Under brine cooling, water (100 L) was added dropwise at an internal temperature of 30 ° C. or lower, and then 35% hydrochloric acid (49.0 kg, 1.6 M / M) was added dropwise at an internal temperature of 30 ° C. or lower. The reaction solution was stirred for 5 minutes and then allowed to stand for 15 minutes or more, and the lower layer (a) was separated into a plastic container. Water (100 L) was added and stirred for 5 minutes, then allowed to stand for 15 minutes or longer. After the lower layer (c) was separated into a plastic container and the upper layer (d) was taken out, the lower layer (a) and the lower layer (c) were returned to the 1500 L reactor. While cooling with brine, ethyl acetate (289 kg) was added, followed by dropwise addition of 48.7% aqueous sodium hydroxide solution (43.4 kg, 1.8 M / M) at an internal temperature of 30 ° C. or lower and stirring for 5 minutes. It was confirmed with UNIV test paper that the pH was 8-9. After leaving still for 15 minutes or more, the lower layer (e) and the upper layer (f) were separated, respectively, and the lower layer (e) was returned to the 1500 L reactor. Ethyl acetate (144 kg) was added and stirred for 5 minutes, then allowed to stand for 15 minutes or longer, and the lower layer (g) and the upper layer (h) were separated. The lower layer (g) was returned to the 1500 L reactor, ethyl acetate (144 kg) was added, stirred for 5 minutes, and allowed to stand for 15 minutes or longer. After taking out the lower layer (i), the upper layer (f) and the upper layer (h) were returned to the 1500 L reactor and washed with ethyl acetate (about 15 kg).
The organic layer returned to the 1500 L reactor was concentrated under reduced pressure (warm water 50 ° C.), and the concentration was temporarily stopped when the concentrated liquid reached about 200 L. The concentrated solution was taken out into a SUS container, and the inside of the can was washed out with toluene (17 kg). About half of the concentrated liquid taken out was placed in a 300 L reactor and washed with toluene (9 kg). The concentrated solution was further concentrated under reduced pressure (hot water 50 ° C.), and when the amount of distillation from the condenser decreased, the remaining concentrated solution was put into a 300 L reaction vessel and washed with toluene (9 kg). Concentration under reduced pressure was resumed (hot water 50 ° C. to 70 ° C.). When almost no distillation occurred, water cooling was started, and toluene (52 kg) was added at an internal temperature of 50 ° C. or lower. Concentration under reduced pressure was resumed (hot water 50-80 ° C.). Concentration was terminated when no distillation was observed at an external temperature of 80 ° C. and a reduced pressure of −0.090 MPa or more, and ethanol (61 kg) was added at an internal temperature of 20-30 ° C.
Under a nitrogen atmosphere, the ethanol solution in the can was taken out into a SUS container and washed with ethanol (13 kg). The solution taken out was added to a 1500 L reactor, and then washed with ethanol (13 kg) to obtain an ethanol solution of the title compound (containing 69.4 kg of the desired product, yield: 107.3%).
HPLC conditions Column: YMC-Pack Pro C18 (5 μm, 150 × 4.6 mm I.D., YMC), mobile phase: acetonitrile / water / ammonium acetate = 300/700/1 to 900/100/1 (v / v / w) .
次いで、ヒドロキシルアミン塩酸塩(40.8kg,2.0M/M)を内温10℃以下で加え、内温10℃以下で1時間以上攪拌した。次に、予め調製し冷却しておいた含水エタノール(エタノール(15.3kg)/水(5.2kg))を発熱に注意しながら内温20℃以下で滴下し、水(582L)を内温30℃以下で滴下した。温水(28℃)循環に切り替え、内温20~30℃でエチル 4-{2-[(2,2-ジメチルプロパノイル)アミノ]ピリジン-3-イル}-2-(ヒドロキシイミノ)-4-オキソブタノエイト(約10g)を加えた。目視にて固体の析出を確認した後、内温15~25℃で終夜攪拌した。反応が終了していることをHPLCにて確認した後、溶液のpHが6.50~7.00になるまで48.7%水酸化ナトリウム水溶液を内温10~25℃で滴下した(18.1kg使用)。内温10~20℃で3時間以上攪拌後、6回に分けて遠心分離機で固液分離を行った。各遠心毎に、予め調製した含水エタノール(エタノール(2.4kg)/水(12kg))でケーキを洗浄した後、洗液の色が無色透明になるまで水(約200L)で洗浄した。さらに30分以上遠心分離を行った後、wet固体をポリ袋に取り出した。次いで、棚式乾燥機にて、45~50℃の温水循環下、減圧乾燥し、固体(71.52kg)を得た。
次に、1500L反応缶に上記で得られた固体(71.45kg)を加え、エタノール(約7kg)で洗い込んだ。続いて、エタノールを合計226kgになるように加え、トリエチルアミン(21.6kg,1M/M)を加えた。温水(75℃)循環を開始し、内温70~75℃で14~16時間攪拌し、反応が終了していることをHPLCにて確認した。次いで、n-ヘプタン(488.7kg)を内温55~75℃で滴下した。その後、内温50~53℃でエチル 5-{2-[(2,2-ジメチルプロパノイル)アミノ]ピリジン-3-イル}イソキサゾール-3-カルボキシレート(約5g)を加え、内温45~50℃で固体が析出していることを目視にて確認した。次いで、温水の温度を徐々に下げ、内温15℃以下まで冷却した後、さらに、ブラインもしくは冷水冷却により内温0~10℃で終夜攪拌した。ろ過機を用いて懸濁液をろ過し、n-ヘプタン/エタノール混合溶液(n-ヘプタン(70kg)/エタノール(10kg))、次いでn-ヘプタン(80kg)で洗浄した。窒素にて15分以上乾燥を行った後、wet固体をSUS容器に取り出した。wet固体を棚式乾燥機にて、45~50℃の温水循環下、減圧乾燥し、標記化合物(54.55kg,収率:58.6%)を得た。
1H-NMR Spectrum (DMSO-d6)δ(ppm):1.19(9H,s), 1.32(3H,t), 4.37(4H,q), 7.12(1H,s), 7.46(1H,dd,J=4.8,8.0Hz), 8.25(1H,dd,J=2.0,8.0Hz), 8.58(1H,dd,J=2.0,4.8Hz), 10.03(1H,s).
HPLC条件 カラム:YMC-Pack Pro C18 (5μm, 150x4.6mmI.D., YMC),移動相:アセトニトリル/水/酢酸アンモニウム=300/700/1~900/100/1(v/v/w)。 [Reference Example 12] Synthesis of ethyl 5- {2-[(2,2-dimethylpropanoyl) amino] pyridin-3-yl} isoxazole-3-carboxylate
Subsequently, hydroxylamine hydrochloride (40.8 kg, 2.0 M / M) was added at an internal temperature of 10 ° C. or lower, and the mixture was stirred at an internal temperature of 10 ° C. or lower for 1 hour or longer. Next, water ethanol (ethanol (15.3 kg) / water (5.2 kg)) prepared and cooled in advance was added dropwise at an internal temperature of 20 ° C. or less while paying attention to heat generation, and water (582 L) was added to the internal temperature. It was dripped at 30 ° C. or lower. Switching to warm water (28 ° C.) circulation, ethyl 4- {2-[(2,2-dimethylpropanoyl) amino] pyridin-3-yl} -2- (hydroxyimino) -4- at an internal temperature of 20-30 ° C. Oxobutanoate (about 10 g) was added. After confirming the precipitation of the solid by visual observation, the mixture was stirred overnight at an internal temperature of 15 to 25 ° C. After confirming the completion of the reaction by HPLC, a 48.7% aqueous sodium hydroxide solution was added dropwise at an internal temperature of 10 to 25 ° C. until the pH of the solution reached 6.50 to 7.00 (18. 1 kg used). After stirring for 3 hours or longer at an internal temperature of 10 to 20 ° C., solid-liquid separation was performed in 6 centrifuges. After each centrifugation, the cake was washed with water-containing ethanol (ethanol (2.4 kg) / water (12 kg)) prepared in advance, and then washed with water (about 200 L) until the color of the washing became colorless and transparent. After further centrifugation for 30 minutes or more, the wet solid was taken out into a plastic bag. Next, it was dried under reduced pressure in a shelf dryer at 45 to 50 ° C. with circulating hot water to obtain a solid (71.52 kg).
Next, the solid (71.45 kg) obtained above was added to a 1500 L reactor and washed with ethanol (about 7 kg). Subsequently, ethanol was added to a total of 226 kg, and triethylamine (21.6 kg, 1 M / M) was added. Warm water (75 ° C.) circulation was started, and the mixture was stirred at an internal temperature of 70 to 75 ° C. for 14 to 16 hours. It was confirmed by HPLC that the reaction was complete. Subsequently, n-heptane (488.7 kg) was added dropwise at an internal temperature of 55 to 75 ° C. Thereafter, ethyl 5- {2-[(2,2-dimethylpropanoyl) amino] pyridin-3-yl} isoxazole-3-carboxylate (about 5 g) was added at an internal temperature of 50 to 53 ° C., and an internal temperature of 45 to It was visually confirmed that a solid was precipitated at 50 ° C. Next, the temperature of the warm water was gradually lowered and cooled to an internal temperature of 15 ° C. or lower, and further stirred overnight at an internal temperature of 0 to 10 ° C. by cooling with brine or cold water. The suspension was filtered using a filter and washed with a mixed solution of n-heptane / ethanol (n-heptane (70 kg) / ethanol (10 kg)) and then n-heptane (80 kg). After drying with nitrogen for 15 minutes or more, the wet solid was taken out into a SUS container. The wet solid was dried under reduced pressure in a shelf dryer under hot water circulation at 45 to 50 ° C. to obtain the title compound (54.55 kg, yield: 58.6%).
1 H-NMR Spectrum (DMSO-d6) δ (ppm): 1.19 (9H, s), 1.32 (3H, t), 4.37 (4H, q), 7.12 (1H, s), 7.46 (1H, dd, J = 4.8, 8.0 Hz), 8.25 (1 H, dd, J = 2.0, 8.0 Hz), 8.58 (1 H, dd, J = 2.0, 4.8 Hz), 10.03 (1 H, s).
HPLC conditions Column: YMC-Pack Pro C18 (5 μm, 150 × 4.6 mm I.D., YMC), mobile phase: acetonitrile / water / ammonium acetate = 300/700/1 to 900/100/1 (v / v / w) .
次いで、水冷却を開始し、内温30℃以下でテトラヒドロフラン(121kg)を加えた。ブライン冷却に切り替え、窒素気流下、水素化ホウ素ナトリウム(7.15kg,1.1M/M)を内温0~10℃で5時間以上かけて分割添加した。水素化ホウ素ナトリウムの添加終了後、ジャケットを冷水(4.0℃)循環に切り替え、内温0~10℃で終夜攪拌した。翌日、水素化ホウ素ナトリウム(1.30kg,0.2M/M)を内温0~10℃で1時間以上かけて分割添加した。ジャケットを冷水に切り替え、3時間以上かけて内温を20~30℃に昇温し、さらに、そのまま内温20~30℃で終夜攪拌を行った。翌日、反応の進行具合をHPLCにて確認したが、反応はほとんど進行していなかったため、再度冷却し、水素化ホウ素ナトリウム(1.30kg,0.2M/M)を内温0~10℃で分割添加した。内温0~10℃で1時間以上攪拌した後、ジャケットを冷水循環に切り替え、2時間以上かけて内温15~25℃に昇温した。1時間以上攪拌した後、反応が終了していることをHPLC(条件1)にて確認し、終夜攪拌した。
翌日、48.7%水酸化ナトリウム水溶液(71kg,5M/M)を内温50℃以下で滴下後、続いて水(133L)を内温50℃以下で滴下した。温水(50~80℃)循環を開始し、内温50~60℃で20時間以上攪拌した後、反応が終了していることをHPLC(条件2)にて確認した。
次いで、水冷却下、水(73L)を滴下した。冷水(15℃)冷却に切り替え、内温15~30℃で[5-(2-アミノピリジン-3-イル)イソキサゾール-3-イル]メタノールを加え、固体の析出を確認後、水(218L)を滴下し、続いてブライン冷却下、35%塩酸(115kg)を内温15~30℃で滴下し、水(3L)で洗い込んだ。内温15~30℃で5分以上攪拌した後、pHメーターにて反応溶液のpHが4.00~5.00であることを確認し、内温15~30℃で1時間以上攪拌した。次いで、溶液のpHが7.00~8.00になるまで48.7%水酸化ナトリウム水溶液を滴下し(17.1 kg使用)、終夜静置した。翌日、撹拌および減圧を開始し、コンデンサーからの留出を確認後、温水(40℃)循環を開始した。温水(35~45℃)、減圧度68cmHg以上、内温30℃以上の条件下、1時間以上濃縮を行った。窒素にて減圧を解除し、水(約20L)で缶壁に付着した固体を洗い込んだ。内温15~30℃で3時間以上撹拌し、終夜静置した。翌日、内温15~25℃の範囲内にあることを確認し、スラリー液を2回にわけて遠心分離機で固液分離した。各遠心毎に、水(約200L)で洗浄し、液切れ後1時間遠心分離を行った後、wet固体をポリ袋に取り出した。次いで、棚式乾燥機にて、45~50℃の温水循環下、減圧乾燥し、標記化合物(26.57kg,収率:80.9%)を得た。
1H-NMR Spectrum (DMSO-d6)δ(ppm):4.54(2H,s), 5.57(1H,brs), 6.25(2H,brs), 6.71(1H,dd,J=4.8,8.0Hz), 6.90(1H,s), 7.90(1H,dd,J=1.6,7.6Hz), 8.09(1H,dd,J=1.6,4.8Hz).
HPLC条件1 カラム:YMC-Pack Pro C18 (5μm, 150x4.6mmI.D., YMC),移動相:アセトニトリル/水/酢酸アンモニウム=300/700/1~900/100/1(v/v/w)。
HPLC条件2 カラム:YMC-Pack ODS-AQ (5μm, 150x4.6mmI.D., YMC),移動相:アセトニトリル/水/85%リン酸/1-オクタンスルホン酸ナトリウム=161.3/838.7/1/1.1~900/100/1/1.1(v/v/v/w)。 Reference Example 13 Synthesis of [5- (2-aminopyridin-3-yl) isoxazol-3-yl] methanol
Next, water cooling was started, and tetrahydrofuran (121 kg) was added at an internal temperature of 30 ° C. or lower. Switching to brine cooling, sodium borohydride (7.15 kg, 1.1 M / M) was added in portions over 5 hours at an internal temperature of 0 to 10 ° C. under a nitrogen stream. After completion of the addition of sodium borohydride, the jacket was switched to cold water (4.0 ° C.) circulation and stirred overnight at an internal temperature of 0 to 10 ° C. On the next day, sodium borohydride (1.30 kg, 0.2 M / M) was added in portions at an internal temperature of 0 to 10 ° C. over 1 hour. The jacket was switched to cold water, the internal temperature was raised to 20-30 ° C. over 3 hours, and stirring was continued overnight at the internal temperature of 20-30 ° C. as it was. On the next day, the progress of the reaction was confirmed by HPLC, but the reaction was hardly proceeding, so it was cooled again and sodium borohydride (1.30 kg, 0.2 M / M) was added at an internal temperature of 0 to 10 ° C. Add in portions. After stirring for 1 hour or more at an internal temperature of 0 to 10 ° C., the jacket was switched to cold water circulation, and the temperature was raised to an internal temperature of 15 to 25 ° C. over 2 hours or more. After stirring for 1 hour or longer, it was confirmed by HPLC (Condition 1) that the reaction was complete, and the mixture was stirred overnight.
The next day, 48.7% aqueous sodium hydroxide solution (71 kg, 5 M / M) was added dropwise at an internal temperature of 50 ° C. or lower, and then water (133 L) was added dropwise at an internal temperature of 50 ° C. or lower. Hot water (50 to 80 ° C.) circulation was started, and the mixture was stirred at an internal temperature of 50 to 60 ° C. for 20 hours or longer. Then, it was confirmed by HPLC (condition 2) that the reaction was complete.
Subsequently, water (73 L) was dripped under water cooling. Switching to cold water (15 ° C.) cooling, [5- (2-aminopyridin-3-yl) isoxazol-3-yl] methanol was added at an internal temperature of 15-30 ° C. After confirming the precipitation of solids, water (218 L) was added. Subsequently, 35% hydrochloric acid (115 kg) was added dropwise at an internal temperature of 15 to 30 ° C. with brine cooling, and washed with water (3 L). After stirring at an internal temperature of 15 to 30 ° C. for 5 minutes or longer, the pH of the reaction solution was confirmed to be 4.00 to 5.00 with a pH meter, and stirred at an internal temperature of 15 to 30 ° C. for 1 hour or longer. Then, a 48.7% aqueous sodium hydroxide solution was added dropwise until the pH of the solution reached 7.00 to 8.00 (17.1 kg used) and left overnight. On the next day, stirring and decompression were started, and after confirming distillation from the condenser, circulation of warm water (40 ° C.) was started. Concentration was performed for 1 hour or more under conditions of warm water (35 to 45 ° C.), a reduced pressure of 68 cmHg or more, and an internal temperature of 30 ° C. or more. The reduced pressure was released with nitrogen, and the solid adhering to the can wall was washed with water (about 20 L). The mixture was stirred at an internal temperature of 15 to 30 ° C. for 3 hours or more and allowed to stand overnight. The next day, it was confirmed that the internal temperature was within the range of 15 to 25 ° C., and the slurry was separated into solid and liquid by a centrifuge in two steps. After each centrifugation, it was washed with water (about 200 L), centrifuged for 1 hour after running out of liquid, and the wet solid was taken out into a plastic bag. Next, the product was dried under reduced pressure in a shelf-type dryer under hot water circulation at 45 to 50 ° C. to obtain the title compound (26.57 kg, yield: 80.9%).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 4.54 (2H, s), 5.57 (1H, brs), 6.25 (2H, brs), 6.71 (1H, dd, J = 4.8, 8.0 Hz) , 6.90 (1H, s), 7.90 (1H, dd, J = 1.6, 7.6Hz), 8.09 (1H, dd, J = 1.6, 4.8Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):4.54(2H,s), 6.31(2H,brs), 6.72(1H,dd,J=4.8,8.0Hz), 6.89(1H,s), 7.90(1H,dd,J=2.0,8.0Hz), 8.09(1H,dd,J=2.0,4.8Hz). [Reference Example 14] Synthesis of [5- (2-aminopyridin-3-yl) isoxazol-3-yl] methanol oxalate
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 4.54 (2H, s), 6.31 (2H, brs), 6.72 (1H, dd, J = 4.8, 8.0 Hz), 6.89 (1H, s) , 7.90 (1H, dd, J = 2.0,8.0Hz), 8.09 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):4.54(2H,s), 5.57(1H,brs), 6.25(2H,brs), 6.71(1H,dd,J=4.8,8.0Hz), 6.90(1H,s), 7.90(1H,dd,J=1.6,7.6Hz), 8.09(1H,dd,J=1.6,4.8Hz). Reference Example 15 Synthesis of [5- (2-aminopyridin-3-yl) isoxazol-3-yl] methanol
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 4.54 (2H, s), 5.57 (1H, brs), 6.25 (2H, brs), 6.71 (1H, dd, J = 4.8, 8.0 Hz) , 6.90 (1H, s), 7.90 (1H, dd, J = 1.6, 7.6Hz), 8.09 (1H, dd, J = 1.6, 4.8Hz).
1H-NMR Spectrum (DMSO-d6)δ(ppm):4.84(2H,s), 6.31(2H,brs), 6.72(1H,dd,J=4.8,8.0Hz), 7.04(1H,s), 7.91(1H,dd,J=1.6,7.6Hz), 8.11(1H,dd,J=1.2,4.8Hz). [Reference Example 16] Synthesis of 3- [3- (chloromethyl) isoxazol-5-yl] pyridin-2-amine
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 4.84 (2H, s), 6.31 (2H, brs), 6.72 (1H, dd, J = 4.8,8.0Hz), 7.04 (1H, s) , 7.91 (1H, dd, J = 1.6, 7.6Hz), 8.11 (1H, dd, J = 1.2, 4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.33(18H,s), 4.63(2H,s), 6.66(1H,s), 7.45(1H,dd,J=4.8,8.0Hz), 8.30(1H,dd,J=2.0,8.0Hz), 8.62(1H,dd,J=2.0,4.8Hz). [Reference Example 17] Synthesis of di-tert-butyl {3- [3- (chloromethyl) isoxazol-5-yl] pyridin-2-yl} imide dicarbonate
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.33 (18H, s), 4.63 (2H, s), 6.66 (1H, s), 7.45 (1H, dd, J = 4.8, 8.0 Hz), 8.30 (1H, dd, J = 2.0,8.0Hz), 8.62 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.47(9H,s), 4.83(2H,s), 6.63(1H,s), 7.17(1H,dd,J=4.8,8.0Hz), 7.58(1H,s), 7.97(1H,dd,J=2.0,8.0Hz), 8.51(1H,dd,J=2.0,4.8Hz). [Reference Example 18] Synthesis of tert-butyl {3- [3- (hydroxymethyl) isoxazol-5-yl] pyridin-2-yl} carbamate
1 H-NMR Spectrum (CDCl3) δ (ppm): 1.47 (9H, s), 4.83 (2H, s), 6.63 (1H, s), 7.17 (1H, dd, J = 4.8, 8.0 Hz), 7.58 ( 1H, s), 7.97 (1H, dd, J = 2.0, 8.0Hz), 8.51 (1H, dd, J = 2.0, 4.8Hz).
窒素雰囲気下、tert-ブチル {3-[3-(ヒドロキシメチル)イソキサゾール-5-イル]ピリジン-2-イル}カルバメート(781mg,2.68mmol)をN,N-ジメチルアセトアミド(2.7mL)に溶解し、氷水冷下、上記した塩化チオニル-ベンゾトリアゾール(1:1.1)のN,N-ジメチルアセトアミド溶液(6mL,14.4mmol)を滴下し、同温で1時間撹拌した後、室温で撹拌した。1時間20分後、氷水冷下、塩化チオニル-ベンゾトリアゾール(1:1.1)のN,N-ジメチルアセトアミド溶液(2.2mL,5.12mmol)を滴下し、室温で1時間撹拌した。氷水冷下、反応液へ1N水酸化ナトリウム水溶液とtert-ブチルメチルエーテルを加え、塩基性とした後、抽出した。有機層を0.5N水酸化ナトリウム水溶液、5%食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した後、減圧下溶媒を留去し、標記化合物の粗体(953mg)を淡黄色油状物として得た。
1H-NMR Spectrum (CDCl3)δ(ppm):1.47(9H,s), 4.65(2H,s), 6.67(1H,s), 7.20(1H,dd,J=4.8,8.0Hz), 7.44(1H,brs), 8.01(1H,dd,J=2.0,8.0Hz), 8.52(1H,dd,J=2.0,4.8Hz). [Reference Example 19] Synthesis of tert-butyl {3- [3- (chloromethyl) isoxazol-5-yl] pyridin-2-yl} carbamate
Under a nitrogen atmosphere, tert-butyl {3- [3- (hydroxymethyl) isoxazol-5-yl] pyridin-2-yl} carbamate (781 mg, 2.68 mmol) was added to N, N-dimethylacetamide (2.7 mL). Dissolve the solution, and add a solution of thionyl chloride-benzotriazole (1: 1.1) in N, N-dimethylacetamide (6 mL, 14.4 mmol) dropwise under ice-water cooling and stir at the same temperature for 1 hour. Stir with. After 1 hour and 20 minutes, a solution of thionyl chloride-benzotriazole (1: 1.1) in N, N-dimethylacetamide (2.2 mL, 5.12 mmol) was added dropwise with ice water cooling, and the mixture was stirred at room temperature for 1 hour. Under cooling with ice water, 1N aqueous sodium hydroxide solution and tert-butyl methyl ether were added to the reaction solution to make it basic, and then extracted. The organic layer was washed successively with 0.5N aqueous sodium hydroxide solution and 5% brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the crude title compound (953 mg) as a pale yellow oil. Obtained.
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.47 (9H, s), 4.65 (2H, s), 6.67 (1H, s), 7.20 (1H, dd, J = 4.8, 8.0 Hz), 7.44 (1H, brs), 8.01 (1H, dd, J = 2.0,8.0Hz), 8.52 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.33(18H,s), 4.63(2H,s), 6.66(1H,s), 7.45(1H,dd,J=4.8,8.0Hz), 8.30(1H,dd,J=2.0,8.0Hz), 8.62(1H,dd,J=2.0,4.8Hz). [Reference Example 20] Synthesis of di-tert-butyl {3- [3- (chloromethyl) isoxazol-5-yl] pyridin-2-yl} imide dicarbonate
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.33 (18H, s), 4.63 (2H, s), 6.66 (1H, s), 7.45 (1H, dd, J = 4.8, 8.0 Hz), 8.30 (1H, dd, J = 2.0,8.0Hz), 8.62 (1H, dd, J = 2.0,4.8Hz).
500L反応缶1の後処理は以下のように実施した。攪拌を開始して水(52kg,2w/w)を加えた後、内温0~25℃で約8%水酸化ナトリウム水溶液(48%水酸化ナトリウム水溶液(11.3kg,水酸化ナトリウムとして135.6mol,1.0M/M)と水(56.5kg,2.17w/w)の混液)を少しずつ滴下し、下層のpHを7.00~8.50(実測値:pH7.84)に調整した。この時、約8%水酸化ナトリウム水溶液は35.55kg使用した。続いて、内温を15~30℃に調整し、30分以上攪拌後、終夜静置した。翌日、pHがpH7.59であることを再度確認した後、上層と下層をそれぞれ分取し、下層のみを500L反応缶1に戻した後、酢酸エチル(82kg,3.15w/w)を加えた。内温15~30℃で5分攪拌後、30分以上静置し、下層(pH7.55)を除去した。缶に残した上層に分取しておいた上層および5%食塩水(食塩(3.3kg,0.13w/w)と水(618kg,2.38w/w)の混液)を加え、内温15~30℃で5分攪拌後、30分以上静置して下層(pH8.23)を除去した。さらに、水(65kg,2.5w/w)を加えて、内温15~30℃で5分攪拌後、終夜静置して下層(pH7.04)を除去した。
500L反応缶2の後処理は、500L反応缶1の操作と並行して同じ作業を実施した。
次に、500L反応缶2の上層を500L反応缶1に移送し、温水45~55℃、減圧度-0.070~-0.085MPaで内容液が約200Lとなるまで減圧濃縮した。ここに酢酸エチル(141kg,5.42w/w)を加えて、再び同条件で減圧濃縮した。この操作をさらに2回繰り返した後、4度目の酢酸エチル(141kg,5.42w/w)を添加する前後でのHPLC分析により内容液の3-[3-(クロロメチル)イソキサゾール-5-イル]ピリジン-2-アミン含量を確認し、内溶液中の3-[3-(クロロメチル)イソキサゾール-5-イル]ピリジン-2-アミン含有量(23.35kg,111.4mol)とその収率(81.9%)を算出した。続いて、もう一度同じ条件で3-[3-(クロロメチル)イソキサゾール-5-イル]ピリジン-2-アミン含量が10.0~13.0%になるまで減圧濃縮を行い、3-[3-(クロロメチル)イソキサゾール-5-イル]ピリジン-2-アミンの酢酸エチル溶液を得た。
窒素気流下,500L反応缶1内の3-[3-(クロロメチル)イソキサゾール-5-イル]ピリジン-2-アミンの酢酸エチル溶液(前工程で得た全量,23.35kg(111.4mol)を含有)を攪拌し、内温15~25℃でジ-tert-ブチルジカーボネイト(53.47kg,245.0mol,2.2M/M)を加え、酢酸エチル(2kg)で洗い込んだ。ここに、あらかじめ調製した4-ジメチルアミノピリジンの酢酸エチル溶液(4-ジメチルアミノピリジン(0.409kg,3.35mol,0.03M/M)と酢酸エチル(8kg)の混液)を加え、酢酸エチル(1kg)で洗い込んだ後、内温10~30℃で22時間以上攪拌した。HPLC分析により反応の終了を確認した後、1,3-ジメチル-2-イミダゾリジノン(50kg,2.12w/w)を加えた。45~55℃の温水循環下、減圧度-0.092MPa以上かつ液留出が弱まるまで減圧濃縮し、GC分析により酢酸エチル含量が7.0%であることを確認後、内温30℃以下まで冷却し、終夜静置した。翌日、濃縮残渣にメタノール(111kg,4.74w/w)を加えて10分以上攪拌し、固体が析出していないことを確認後、溶液を2分割した。次に2分割した溶液を500L反応缶1及び2にそれぞれ加え、それぞれメタノール(各9kg,各0.4w/w)で洗い込んだ。この際、2分割する前の溶液(225.65kg)をHPLC分析した結果、目的のジ-tert-ブチル {3-[3-(クロロメチル)イソキサゾール-5-イル]ピリジン-2-イル}イミドジカーボネート含量は19.37%、含まれているジ-tert-ブチル {3-[3-(クロロメチル)イソキサゾール-5-イル]ピリジン-2-イル}イミドジカーボネート重量は43.71kg(106.6mol,収率:95.7%)であった。
500L反応缶1について、以下のように処理した。攪拌を開始後、内温35~45℃で水(35kg,1.5w/w)を30分以上かけて滴下し、内温35~40℃でジ-tert-ブチル {3-[3-(クロロメチル)イソキサゾール-5-イル]ピリジン-2-イル}イミドジカーボネート(0.010kg)を加えた。内温35~40℃で30分以上攪拌後、固体の析出を確認し、さらに同温度範囲で1時間以上攪拌した。続いて、内温35~45℃で水(35kgを3回,各1.5w/w)をそれぞれ30分以上かけて滴下した後、3時間以上かけて内温5~15℃まで冷却し、同温度範囲で12時間以上攪拌した。遠心分離機で2回に分けて固液分離し、含水メタノール(メタノール(1回につき7kg,0.3w/w)と水(1回につき27kg,1.14w/w)の混液)で洗浄した。洗浄終了後、30分以上遠心分離を行い、標記化合物のwet固体(25.80kg)を得た。このwet固体を混合型真空乾燥機に投入し、外温45~55℃で24時間以上真空乾燥し、標記化合物(21.09kg)を淡黄色固体として得た。
500L反応缶2について、上記と並行して同じ操作を行い、標記化合物(21.22kg)を淡黄色固体として得た。
以上より、標記化合物(42.31kg,収率:92.7%)を得た。
1H-NMR Spectrum (CDCl3)δ(ppm):1.33(18H,s), 4.63(2H,s), 6.66(1H,s), 7.45(1H,dd,J=4.8,8.0Hz), 8.30(1H,dd,J=2.0,8.0Hz), 8.62(1H,dd,J=2.0,4.8Hz).
HPLC条件 カラム:YMC-Pack Pro C18 (5μm, 150x4.6mmI.D., YMC),移動相:アセトニトリル/水/酢酸アンモニウム=300/700/1~900/100/1(v/v/w)。
GC条件 カラム:DB-624 (30m, 0.53mmI.D., Film 3μm, Agilent)。 [Reference Example 21] Synthesis of di-tert-butyl {3- [3- (chloromethyl) isoxazol-5-yl] pyridin-2-yl} imide dicarbonate
The post-treatment of the 500
In the post-treatment of the 500
Next, the upper layer of the 500
Ethyl acetate solution of 3- [3- (chloromethyl) isoxazol-5-yl] pyridin-2-amine in a 500
About 500L reaction can 1, it processed as follows. After starting stirring, water (35 kg, 1.5 w / w) was added dropwise at an internal temperature of 35 to 45 ° C. over 30 minutes, and di-tert-butyl {3- [3- ( Chloromethyl) isoxazol-5-yl] pyridin-2-yl} imide dicarbonate (0.010 kg) was added. After stirring at an internal temperature of 35 to 40 ° C. for 30 minutes or longer, solid precipitation was confirmed, and the mixture was further stirred at the same temperature range for 1 hour or longer. Subsequently, water (35 kg three times, 1.5 w / w each) was added dropwise over 30 minutes at an internal temperature of 35 to 45 ° C., and then cooled to an internal temperature of 5 to 15 ° C. over 3 hours. The mixture was stirred for 12 hours or more in the same temperature range. Solid-liquid separation was carried out in two portions with a centrifuge and washed with hydrous methanol (mixture of methanol (7 kg, 0.3 w / w) and water (27 kg, 1.14 w / w) at a time). . After washing, the mixture was centrifuged for 30 minutes or more to obtain a wet solid (25.80 kg) of the title compound. This wet solid was put into a mixed vacuum dryer and vacuum-dried at an external temperature of 45 to 55 ° C. for 24 hours or more to obtain the title compound (21.09 kg) as a pale yellow solid.
For 500
From the above, the title compound (42.31 kg, yield: 92.7%) was obtained.
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.33 (18H, s), 4.63 (2H, s), 6.66 (1H, s), 7.45 (1H, dd, J = 4.8, 8.0 Hz), 8.30 (1H, dd, J = 2.0,8.0Hz), 8.62 (1H, dd, J = 2.0,4.8Hz).
HPLC conditions Column: YMC-Pack Pro C18 (5 μm, 150 × 4.6 mm I.D., YMC), mobile phase: acetonitrile / water / ammonium acetate = 300/700/1 to 900/100/1 (v / v / w) .
GC conditions Column: DB-624 (30 m, 0.53 mm I.D., Film 3 μm, Agilent).
1H-NMR Spectrum (CDCl3)δ(ppm):1.44(3H,t,J=6.8Hz), 1.46(9H,s), 4.47(4H,q,J=7.2Hz), 6.95(1H,s), 7.22(1H,dd,J=4.8,8.0Hz), 7.42(1H,bs), 8.05(1H,dd,J=2.0,8.0Hz), 8.52(1H,dd,J=2.0,4.8Hz). [Reference Example 22] Ethyl 5- {2-[(2,2-dimethylpropoxycarbonyl) amino] pyridin-3-yl} isoxazole-3-carboxylate
1 H-NMR Spectrum (CDCl3) δ (ppm): 1.44 (3H, t, J = 6.8Hz), 1.46 (9H, s), 4.47 (4H, q, J = 7.2Hz), 6.95 (1H, s) , 7.22 (1H, dd, J = 4.8,8.0Hz), 7.42 (1H, bs), 8.05 (1H, dd, J = 2.0,8.0Hz), 8.52 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.36(18H,s), 1.46(3H,t,J=6.8Hz), 4.47(4H,q,J=6.8Hz), 6.93(1H,s), 7.46(1H,dd,J=4.8,7.6Hz), 8.29(1H,d,J=7.6Hz), 8.64(1H,d,J=4.8Hz). [Reference Example 23] Ethyl 5- {2- [bis (2,2-dimethylpropoxycarbonyl) amino] pyridin-3-yl} isoxazole-3-carboxylate
1 H-NMR Spectrum (CDCl3) δ (ppm): 1.36 (18H, s), 1.46 (3H, t, J = 6.8Hz), 4.47 (4H, q, J = 6.8Hz), 6.93 (1H, s) , 7.46 (1H, dd, J = 4.8, 7.6Hz), 8.29 (1H, d, J = 7.6Hz), 8.64 (1H, d, J = 4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.33(18H,s), 4.81(2H,s), 6.60(1H,s), 7.43(1H,dd,J=4.8,8.0Hz), 8.27(1H,dd,J=2.0,8.0Hz), 8.60(1H,dd,J=2.0,4.8Hz). [Reference Example 24] Di-tert-butyl {3- [3- (hydroxymethyl) isoxazol-5-yl] pyridin-2-yl} imide dicarbonate
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.33 (18H, s), 4.81 (2H, s), 6.60 (1H, s), 7.43 (1H, dd, J = 4.8, 8.0 Hz), 8.27 (1H, dd, J = 2.0,8.0Hz), 8.60 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):1.33(18H,s), 4.45(2H,s), 6.63(1H,s), 7.43(1H,dd,J=4.8,8.0Hz), 8.28(1H,dd,J=2.0,8.0Hz), 8.61(1H,dd,J=2.0,4.8Hz). [Reference Example 25] Di-tert-butyl {3- [3- (bromomethyl) isoxazol-5-yl] pyridin-2-yl} imide dicarbonate
1 H-NMR Spectrum (CDCl3) δ (ppm): 1.33 (18H, s), 4.45 (2H, s), 6.63 (1H, s), 7.43 (1H, dd, J = 4.8, 8.0 Hz), 8.28 ( 1H, dd, J = 2.0,8.0Hz), 8.61 (1H, dd, J = 2.0,4.8Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):5.33(2H,s), 6.87-6.70(1H,m), 6.98-7.02(1H,m), 7.38-7.44(2H,m), 7.55-7.60(2H,m), 7.71-7.76(1H,m), 8.15-8.18(1H,m). [Reference Example 26] Synthesis of 2-[(4-bromobenzyl) oxy] pyridine
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 5.33 (2H, s), 6.87-6.70 (1H, m), 6.98-7.02 (1H, m), 7.38-7.44 (2H, m), 7.55- 7.60 (2H, m), 7.71-7.76 (1H, m), 8.15-8.18 (1H, m).
1H-NMR Spectrum (CDCl3)δ(ppm):5.33(2H,s), 6.87-6.70(1H,m), 6.98-7.02(1H,m), 7.38-7.44(2H,m), 7.55-7.60(2H,m), 7.71-7.76(1H,m), 8.15-8.18(1H,m). [Reference Example 27] Synthesis of 2-[(4-bromobenzyl) oxy] pyridine
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 5.33 (2H, s), 6.87-6.70 (1H, m), 6.98-7.02 (1H, m), 7.38-7.44 (2H, m), 7.55- 7.60 (2H, m), 7.71-7.76 (1H, m), 8.15-8.18 (1H, m).
1H-NMR Spectrum (CDCl3)δ(ppm):4.62(2H,s), 5.42(2H,s), 6.83(1H,d,J=8.4Hz), 6.87-6.92(1H,m), 7.50(2H,d,J=8.0Hz), 7.57-7.62(1H,m), 7.75(2H,d,J=8.0Hz), 8.16-8.19(1H,m). [Reference Example 28] Synthesis of {4-[(pyridine-2-yloxy) methyl] phenyl} boronic acid
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 4.62 (2H, s), 5.42 (2H, s), 6.83 (1H, d, J = 8.4 Hz), 6.87-6.92 (1H, m), 7.50 (2H, d, J = 8.0Hz), 7.57-7.62 (1H, m), 7.75 (2H, d, J = 8.0Hz), 8.16-8.19 (1H, m).
1H-NMR Spectrum (DMSO-d6)δ(ppm):0.94(6H,s), 3.74(4H,s), 5.35(2H,s), 6.87(1H,d,J=8.4Hz), 6.96-7.00(1H,m), 7.39(2H,d,J=8.0Hz), 7.67-7.74(3H,m), 8.14-8.17(1H,m). [Reference Example 29] Synthesis of 2-{[4- (5,5-dimethyl-1,3,2-dioxaborin-2-yl) benzyl] oxy} pyridine
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 0.94 (6H, s), 3.74 (4H, s), 5.35 (2H, s), 6.87 (1H, d, J = 8.4 Hz), 6.96 -7.00 (1H, m), 7.39 (2H, d, J = 8.0Hz), 7.67-7.74 (3H, m), 8.14-8.17 (1H, m).
1H-NMR Spectrum (CDCl3)δ(ppm):1.23(9H,s), 4.05(2H,s), 5.34(2H,s), 6.32(1H,s), 6.76-6.79(1H,m), 6.86-6.90(1H,m), 7.28(2H,d, J=8.0Hz), 7.38-7.43(3H,m), 7.55-7.60(1H,m), 8.15-8.18(1H,m), 8.27(1H,dd,J=2.0,8.0Hz), 8.57(1H,dd,J=2.0,7.6Hz). [Reference Example 30] Synthesis of di-tert-butyl [3- (3- {4 [(pyridin-2-yloxy) methyl] benzyl} isoxazol-5-yl) pyridin-2-yl] imide dicarbonate
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.23 (9H, s), 4.05 (2H, s), 5.34 (2H, s), 6.32 (1H, s), 6.76-6.79 (1H, m) , 6.86-6.90 (1H, m), 7.28 (2H, d, J = 8.0Hz), 7.38-7.43 (3H, m), 7.55-7.60 (1H, m), 8.15-8.18 (1H, m), 8.27 (1H, dd, J = 2.0,8.0Hz), 8.57 (1H, dd, J = 2.0,7.6Hz).
1H-NMR Spectrum (CDCl3)δ(ppm):4.07(2H,s), 5.37(2H,s), 5.42(2H,brs), 6.25(1H,s), 6.71(1H,dd,J=5.2,7.6Hz), 6.80(1H,d,J=8.4Hz), 6.87-6.91(1H,m), 7.30(2H,d,J=7.6Hz), 7.44(2H,d,J=7.6Hz), 7.56-7.61(1H,m), 7.70(1H,dd,J=2.0,7.6Hz), 8.14(1H,dd,J=2.0,4.8Hz), 8.16-8.19(1H,m). [Reference Example 31] 3- (3- (4-Pyridin-2-yloxymethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 4.07 (2H, s), 5.37 (2H, s), 5.42 (2H, brs), 6.25 (1H, s), 6.71 (1H, dd, J = 5.2,7.6Hz), 6.80 (1H, d, J = 8.4Hz), 6.87-6.91 (1H, m), 7.30 (2H, d, J = 7.6Hz), 7.44 (2H, d, J = 7.6Hz) 7.56-7.61 (1H, m), 7.70 (1H, dd, J = 2.0,7.6Hz), 8.14 (1H, dd, J = 2.0,4.8Hz), 8.16-8.19 (1H, m).
2バッチ目として上記と同様の操作を実施した。2バッチ目のろ液及び洗液を500L反応缶1に加え、1バッチ目の濃縮残渣と合わせて減圧濃縮を開始した。60~70℃の温水循環下、留出が弱まったところで、トルエン(144kg)を添加した後、再度、60~70℃の温水循環下、留出が弱まるまで減圧濃縮した。ここで、濃縮残渣を分析し、濃縮残渣中のジ-tert-ブチル [3-(3-{4[(ピリジン-2-イロキシ)メチル]ベンジル}イソキサゾール-5-イル)ピリジン-2-イル]イミドジカーボネート含量及びトルエン含量からトルエン/目的物の比率(0.167w/w)を算出した。トルエン(29.66kg,トルエン/目的物の比率0.700w/w相当)を添加し、内温15~30℃で30分以上攪拌して、標記化合物のトルエン溶液(目的物を42.37kg含有,収率:74.7%)を得た。
HPLC条件 カラム:CAPCELL PAK C18 MGII (5μm, 150x4.6mmI.D., SHISEIDO),移動相:アセトニトリル/水/トリフルオロ酢酸=180/820/1~900/100/1(v/v/v)。 [Reference Example 32] Synthesis of di-tert-butyl [3- (3- {4 [(pyridin-2-yloxy) methyl] benzyl} isoxazol-5-yl) pyridin-2-yl] imide dicarbonate
The same operation as described above was performed as the second batch. The filtrate and washing solution of the second batch were added to the 500
HPLC conditions Column: CAPCELL PAK C18 MGII (5 μm, 150 × 4.6 mm I.D., SHISEIDO), mobile phase: acetonitrile / water / trifluoroacetic acid = 180/820/1 to 900/100/1 (v / v / v) .
500L反応缶1について、以下のように後処理を実施した。攪拌下、内温-5~20℃で水(74kg,1.75w/w)を滴下し、さらに内温0~25℃でtert-ブチルメチルエーテル(31.4kg,0.74w/w)とn-ヘプタン(29.0kg,0.684w/w)を加えた。内温15~25℃で5分攪拌し、30分以上静置して下層を分取した。下層を缶に戻し、再び内温0~25℃でtert-ブチルメチルエーテル(31.4kg,0.74w/w)とn-ヘプタン(29.0kg,0.684w/w)を加え、内温15~25℃で5分攪拌後、30分以上静置して、もう一度下層を分取した。下層を缶に戻し、まず、内温0~25℃で48%水酸化ナトリウム水溶液(116kg,水酸化ナトリウムとして1392.0mol,18.35M/M)を滴下した。次に、同温度範囲で酢酸エチル(96kg,2.26w/w)を加え、48%水酸化ナトリウム水溶液(20.5kg,水酸化ナトリウムとして246.0mol,3.24M/M)を滴下した。さらに、ここに同温度範囲で約8%水酸化ナトリウム水溶液(48%水酸化ナトリウム水溶液(12.7kg,水酸化ナトリウムとして152.4mol,2.00M/M)と水(64kg,1.5w/w)の混液)を下層のpHがpH8.00~9.00,実測値:pH8.58)となるまで滴下した(0.75kg使用)。その後、内温20~30℃で1時間以上攪拌してから終夜静置後、下層のpHを再確認(実測値pH8.29)し、下層を除去した。缶に残った上層に約5%炭酸水素ナトリウム水溶液(炭酸水素ナトリウム(5.3kg,63.09mol)と水(101kg,2.375w/w)の混液)を加え、内温20~30℃で1時間以上攪拌後、30分以上静置した。下層(pH8.60)を除去した後、上層に水(106kg,2.5w/w)を加え、内温20~30℃で1時間以上攪拌後、30分以上静置して、再び下層(pH7.17)を除去した。
500L反応缶2について、500L反応缶1と並行して同様の後処理を実施した。
500L反応缶1の内容液を500L反応缶2に移送し、55~65℃の温水循環下、内容液が約100Lとなるまで減圧濃縮した。次に、濃縮残渣にエタノール(42kg,1.0w/w)と酢酸エチル(96kg,2.26w/w)を加え5分攪拌した後、55~65℃の温水循環下、減圧度-0.092MPa以上でほぼ留出を認めなくなるまで減圧濃縮した。ここで、結晶の析出を認めたため、結晶が完全に溶解するまで少しずつ酢酸エチルを加えた(13.85kg使用)。さらにエタノール(18.3kg)及び酢酸エチル(6.7kg)を加えた後、内温を50~55℃に調整し、結晶が溶解していることを目視にて確認後、内温45~55℃でn-ヘプタン(33.5kg,0.79w/w)を30分以上かけて滴下した。続いて、内温45~50℃で、国際公開第08/136279号パンフレットの明細書実施例18に記載の方法で合成できる3-(3-(4-ピリジン-2-イルオキシメチル)-ベンジル)-イソキサゾール-5-イル)-ピリジン-2-イルアミン(0.011kg)を加え、結晶の析出を確認後、同温度範囲で1時間以上攪拌した。内温45~55℃でn-ヘプタン(66.9kg,1.58w/w)を1時間以上かけて滴下した後、4時間以上かけて内温0~10℃まで冷却し、同温度範囲で5時間以上攪拌した。内容液をサンプリングし、目的物の結晶化率が94%であることを確認した後、懸濁液を加圧ろ過し、結晶をエタノール-酢酸エチル-n-ヘプタン混液(エタノール(3.60kg,0.085w/w)と酢酸エチル(4.15kg,0.098w/w)とn-ヘプタン(18.81kg,0.444w/w)の混液)、エタノール-n-ヘプタン混液(エタノール(7.25kg,0.171w/w)とn-ヘプタン(18.81kg,0.444w/w)の混液)の順にかけ洗いを行い、標記化合物のwet粗結晶(36.52kg)を微黄色結晶として得た。
あらかじめ窒素置換した500L溶解缶に、得られた3-(3-(4-ピリジン-2-イルオキシメチル)-ベンジル)-イソキサゾール-5-イル)-ピリジン-2-イルアミンのwet粗結晶(36.52kg)およびエタノール(57.9kg,2.37w/w)を順次加え、内温70~75℃まで加熱し、結晶を溶解させた。この溶解液を保温したままSUSフィルターを通じて500L晶析缶へ移送し、外温約65℃で温めておいたエタノール(19.3kg,0.8w/w)で500L溶解缶及びSUSフィルターを洗い込んだ。次に、ろ液を内温55~60℃に調整して、缶内の溶液が均一であることを確認した。その後、内温をゆっくりと48~51℃まで冷却したところ、結晶が析出した。再度、内温55~60℃まで加熱して結晶を溶解した後、速やかに内温48~51℃まで冷却し、直ちに、国際公開第08/136279号パンフレットの明細書実施例18に記載の方法で合成できる3-(3-(4-ピリジン-2-イルオキシメチル)-ベンジル)-イソキサゾール-5-イル)-ピリジン-2-イルアミン(0.011kg)を加えた。続いて、内温45~50℃で結晶の析出を目視にて確認後、内温43~47℃で1時間~1時間30分攪拌し、4時間以上かけて内温0~10℃まで冷却した。ここで、析出した結晶をサンプリングし、その結晶形が標準品と同一であることを確認した後、同温度範囲で終夜攪拌した。翌日、結晶形が標準品と同一であることを確認した後、結晶を遠心分離機で2回に分けて固液分離し、それぞれエタノール19.3kgの約1/2量でかけ洗い、目的物のwet結晶(24.23kg)を得た。このwet結晶を混合型真空乾燥機に投入し、外温20~30℃で6時間以上、外温35~45℃で12時間以上減圧乾燥し、標記化合物(23.52kg,65.63mol,収率:86.8%)を淡黄色結晶として得た。
1H-NMR Spectrum (CDCl3)δ(ppm):4.07(2H,s), 5.37(2H,s), 5.42(2H,brs), 6.25(1H,s), 6.71(1H,dd,J=5.2,7.6Hz), 6.80(1H,d,J=8.4Hz), 6.87-6.91(1H,m), 7.30(2H,d,J=7.6Hz), 7.44(2H,d,J=7.6Hz), 7.56-7.61(1H,m), 7.70(1H,dd,J=2.0,7.6Hz), 8.14(1H,dd,J=2.0,4.8Hz), 8.16-8.19(1H,m).
HPLC条件 カラム:CAPCELL PAK C18 MGII (5μm, 150x4.6mmI.D., SHISEIDO),移動相:アセトニトリル/水/トリフルオロ酢酸=180/820/1~900/100/1(v/v/v)。 [Reference Example 33] 3- (3- (4-Pyridin-2-yloxymethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine
About 500L reaction can 1, the post-processing was implemented as follows. Under stirring, water (74 kg, 1.75 w / w) was added dropwise at an internal temperature of -5 to 20 ° C., and tert-butyl methyl ether (31.4 kg, 0.74 w / w) was added at an internal temperature of 0 to 25 ° C. n-Heptane (29.0 kg, 0.684 w / w) was added. The mixture was stirred at an internal temperature of 15 to 25 ° C. for 5 minutes and allowed to stand for 30 minutes or more to separate the lower layer. Return the lower layer to the can, and again add tert-butyl methyl ether (31.4 kg, 0.74 w / w) and n-heptane (29.0 kg, 0.684 w / w) at an internal temperature of 0 to 25 ° C. After stirring at 15 to 25 ° C. for 5 minutes, the mixture was allowed to stand for 30 minutes or more, and the lower layer was separated again. The lower layer was returned to the can, and a 48% aqueous sodium hydroxide solution (116 kg, 1392.0 mol, 18.35 M / M as sodium hydroxide) was first added dropwise at an internal temperature of 0 to 25 ° C. Next, ethyl acetate (96 kg, 2.26 w / w) was added in the same temperature range, and a 48% aqueous sodium hydroxide solution (20.5 kg, 246.0 mol as sodium hydroxide, 3.24 M / M) was added dropwise. Furthermore, about 8% sodium hydroxide aqueous solution (48% sodium hydroxide aqueous solution (12.7 kg, 152.4 mol as sodium hydroxide, 2.00 M / M)) and water (64 kg, 1.5 w / m) in the same temperature range. The mixture (w) was added dropwise until the lower layer had a pH of 8.00 to 9.00 (actual value: pH 8.58) (0.75 kg used). Thereafter, the mixture was stirred at an internal temperature of 20 to 30 ° C. for 1 hour or more and allowed to stand overnight, and then the pH of the lower layer was reconfirmed (actual measurement pH 8.29), and the lower layer was removed. About 5% aqueous sodium hydrogen carbonate solution (mixture of sodium hydrogen carbonate (5.3 kg, 63.09 mol) and water (101 kg, 2.375 w / w)) was added to the upper layer remaining in the can, and the internal temperature was 20-30 ° C. After stirring for 1 hour or longer, the mixture was allowed to stand for 30 minutes or longer. After removing the lower layer (pH 8.60), water (106 kg, 2.5 w / w) was added to the upper layer, stirred for 1 hour or more at an internal temperature of 20 to 30 ° C., and then allowed to stand for 30 minutes or more. pH 7.17) was removed.
About 500L reaction can 2, the same post-process was implemented in parallel with 500L reaction can 1.
The content liquid in the 500
Into a 500-L dissolving can previously purged with nitrogen, the obtained wet crude crystals of 3- (3- (4-pyridin-2-yloxymethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine (36 .52 kg) and ethanol (57.9 kg, 2.37 w / w) were sequentially added and heated to an internal temperature of 70 to 75 ° C. to dissolve the crystals. This dissolved solution was transferred to a 500 L crystallization can through a SUS filter while being kept warm, and the 500 L dissolving can and the SUS filter were washed with ethanol (19.3 kg, 0.8 w / w) heated at an external temperature of about 65 ° C. It is. Next, the filtrate was adjusted to an internal temperature of 55-60 ° C., and it was confirmed that the solution in the can was uniform. Thereafter, when the internal temperature was slowly cooled to 48 to 51 ° C., crystals were precipitated. After heating again to an internal temperature of 55 to 60 ° C. to dissolve the crystals, the crystal is promptly cooled to an internal temperature of 48 to 51 ° C., and immediately, the method described in the specification Example 18 of WO08 / 136279 3- (3- (4-Pyridin-2-yloxymethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine (0.011 kg), which can be synthesized by: Subsequently, after visually confirming the precipitation of crystals at an internal temperature of 45 to 50 ° C., the mixture was stirred at an internal temperature of 43 to 47 ° C. for 1 hour to 1 hour and 30 minutes, and then cooled to an internal temperature of 0 to 10 ° C. over 4 hours. did. Here, the precipitated crystals were sampled, and after confirming that the crystal form was the same as the standard product, the crystals were stirred overnight in the same temperature range. The next day, after confirming that the crystal form was the same as that of the standard product, the crystal was separated into solid and liquid by centrifuge twice and washed with about 1/2 amount of 19.3 kg of ethanol. A wet crystal (24.23 kg) was obtained. The wet crystals were put into a mixed vacuum dryer and dried under reduced pressure at an external temperature of 20 to 30 ° C. for 6 hours or longer and at an external temperature of 35 to 45 ° C. for 12 hours or longer to obtain the title compound (23.52 kg, 65.63 mol, yield). Ratio: 86.8%) was obtained as pale yellow crystals.
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 4.07 (2H, s), 5.37 (2H, s), 5.42 (2H, brs), 6.25 (1H, s), 6.71 (1H, dd, J = 5.2,7.6Hz), 6.80 (1H, d, J = 8.4Hz), 6.87-6.91 (1H, m), 7.30 (2H, d, J = 7.6Hz), 7.44 (2H, d, J = 7.6Hz) 7.56-7.61 (1H, m), 7.70 (1H, dd, J = 2.0,7.6Hz), 8.14 (1H, dd, J = 2.0,4.8Hz), 8.16-8.19 (1H, m).
HPLC conditions Column: CAPCELL PAK C18 MGII (5 μm, 150 × 4.6 mm I.D., SHISEIDO), mobile phase: acetonitrile / water / trifluoroacetic acid = 180/820/1 to 900/100/1 (v / v / v) .
1H-NMR Spectrum (DMSO-d6)δ(ppm): 1.91-2.05(2H,m), 2.44-2.57(2H,m), 3.91(1H,brs), 4.03(2H,s), 5.32(2H,s), 6.66(1H,s), 6.84-6.87(1H,m), 6.98-7.01(1H,m), 7.31(2H,d,J=8.1Hz), 7.40-7.44(3H,m), 7.70-7.75(1H,m), 8.16-8.18(2H,m), 8.26(3H,brs), 8.52(1H,dd,J=1.8,4.7Hz), 10.49(1H,s). (S) -2-t-butoxycarbonylamino-4- (3- (3- (4- (pyridin-2-yloxymethyl) -benzyl) -isoxazol-5-yl) described in Preparation Example 1-1 To a mixture of -pyridin-2-ylcarbamoyl) -butyric acid t-butyl ester (980 mg, 1.5 mmol) and dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) at 0 ° C., and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain the title compound (850 mg) as a trifluoroacetate salt.
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 1.91-2.05 (2H, m), 2.44-2.57 (2H, m), 3.91 (1H, brs), 4.03 (2H, s), 5.32 ( 2H, s), 6.66 (1H, s), 6.84-6.87 (1H, m), 6.98-7.01 (1H, m), 7.31 (2H, d, J = 8.1Hz), 7.40-7.44 (3H, m) , 7.70-7.75 (1H, m), 8.16-8.18 (2H, m), 8.26 (3H, brs), 8.52 (1H, dd, J = 1.8,4.7Hz), 10.49 (1H, s).
1H-NMR Spectrum (CDCl3)δ(ppm): 1.42(9H,s), 1.46(9H,s), 1.95(1H,brs), 2.23(1H,brs), 2.64-2.66(2H,m), 4.08(2H,s), 4.23(1H,brs), 5.27(1H,d,J=7.1Hz), 5.36(2H,s), 6.33(1H,s), 6.71-6.81(1H,m), 6.87-6.90(1H,m), 7.18(1H,dd,J=4.7,7.8Hz), 7.30(2H,d,J=8.1Hz), 7.44(2H,d,J=8.1Hz), 7.56-7.61(1H,m), 7.93(1H,d,J=7.9Hz), 8.16-8.18(1H,m), 8.47-8.48(1H,m), 8.52(1H,brs). 3- (3- (4- (Pyridin-2-yloxymethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine (900 mg, 2.5 mmol) described in Reference Example 1 in acetonitrile (15 mL ) Solution at 0 ° C. with (S) -2-t-butoxycarbonylamino-pentanedioic acid 1-t-butyl ester (860 mg, 2.8 mmol), triethylamine (0.37 mL, 2.6 mmol), and O -(7-Azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (1.1 g, 2.8 mmol) was added, and the mixture was stirred at 60 ° C. overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was washed with saturated brine. The obtained residue was purified by NH-silica gel column chromatography (heptane: ethyl acetate = 4: 1) to obtain the title compound (980 mg).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.42 (9H, s), 1.46 (9H, s), 1.95 (1H, brs), 2.23 (1H, brs), 2.64-2.66 (2H, m) , 4.08 (2H, s), 4.23 (1H, brs), 5.27 (1H, d, J = 7.1Hz), 5.36 (2H, s), 6.33 (1H, s), 6.71-6.81 (1H, m), 6.87-6.90 (1H, m), 7.18 (1H, dd, J = 4.7,7.8Hz), 7.30 (2H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz), 7.56-7.61 (1H, m), 7.93 (1H, d, J = 7.9Hz), 8.16-8.18 (1H, m), 8.47-8.48 (1H, m), 8.52 (1H, brs).
1H-NMR Spectrum (DMSO-d6)δ(ppm): 1.97-2.03(2H,m), 2.43-2.53(2H,m), 3.74(3H,s), 4.04-4.05(3H,m), 5.32(2H,s), 6.66(1H,s), 6.84-6.87(1H,m), 6.98-7.01(1H,m), 7.31(2H,d,J=8.2Hz), 7.41(2H,d,J=8.1Hz), 7.43(1H,d,J=7.9Hz), 7.70-7.75(1H,m), 8.16(1H,d,J=1.8Hz), 8.18(1H,t,J=1.8Hz), 8.38(3H,brs), 8.52(1H,dd,J=1.8,4.8Hz), 10.47(1H,s).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 1.97-2.03 (2H, m), 2.43-2.53 (2H, m), 3.74 (3H, s), 4.04-4.05 (3H, m), 5.32 (2H, s), 6.66 (1H, s), 6.84-6.87 (1H, m), 6.98-7.01 (1H, m), 7.31 (2H, d, J = 8.2Hz), 7.41 (2H, d, J = 8.1Hz), 7.43 (1H, d, J = 7.9Hz), 7.70-7.75 (1H, m), 8.16 (1H, d, J = 1.8Hz), 8.18 (1H, t, J = 1.8Hz) , 8.38 (3H, brs), 8.52 (1H, dd, J = 1.8,4.8Hz), 10.47 (1H, s).
1H-NMR Spectrum (CDCl3)δ(ppm): 1.43(9H,s), 1.92-2.01(1H,m), 2.18-2.23(1H,m), 2.39-2.51(2H,m), 3.73(3H,s), 4.34-4.36(1H,m), 5.10-5.12(3H,m), 7.31-7.39(5H,m).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.43 (9H, s), 1.92-2.01 (1H, m), 2.18-2.23 (1H, m), 2.39-2.51 (2H, m), 3.73 ( 3H, s), 4.34-4.36 (1H, m), 5.10-5.12 (3H, m), 7.31-7.39 (5H, m).
1H-NMR Spectrum (CDCl3)δ(ppm): 1.42(9H,s), 1.97-2.04(1H,m), 2.22-2.31(1H,m), 2.67-2.70(2H,m), 3.73(3H,s), 4.08(2H,s), 4.36-4.37(1H,m), 5.34-5.36(3H,m), 6.34(1H,s), 6.79-6.81(1H,m), 6.87-6.90(1H,m), 7.18(1H,dd,J=4.8,7.9Hz), 7.30(2H,d,J=8.1Hz), 7.44(2H,d,J=8.1Hz), 7.56-7.61(1H,m), 7.94(1H,dd,J=1.8,7.8Hz), 8.16-8.18(1H,m), 8.47-8.48(2H,m).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.42 (9H, s), 1.97-2.04 (1H, m), 2.22-2.31 (1H, m), 2.67-2.70 (2H, m), 3.73 ( 3H, s), 4.08 (2H, s), 4.36-4.37 (1H, m), 5.34-5.36 (3H, m), 6.34 (1H, s), 6.79-6.81 (1H, m), 6.87-6.90 ( 1H, m), 7.18 (1H, dd, J = 4.8,7.9Hz), 7.30 (2H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz), 7.56-7.61 (1H, m ), 7.94 (1H, dd, J = 1.8,7.8Hz), 8.16-8.18 (1H, m), 8.47-8.48 (2H, m).
1H-NMR Spectrum (DMSO-d6)δ(ppm): 2.06(2H,brs), 2.49-2.54(2H,m), 2.84(6H,s), 3.44(2H,brs), 4.04-4.08(3H,m), 4.44-4.47(2H,m), 5.32(2H,s), 6.69(1H,s), 6.85(1H,dd,J=0.7,8.4Hz), 6.98-7.01(1H,m), 7.31(2H,d,J=8.1Hz), 7.41-7.45(3H,m), 7.70-7.75(1H,m), 8.16-8.19(2H,m), 8.52-8.53(4H,m), 10.48(1H,s).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 2.06 (2H, brs), 2.49-2.54 (2H, m), 2.84 (6H, s), 3.44 (2H, brs), 4.04-4.08 ( 3H, m), 4.44-4.47 (2H, m), 5.32 (2H, s), 6.69 (1H, s), 6.85 (1H, dd, J = 0.7,8.4Hz), 6.98-7.01 (1H, m) , 7.31 (2H, d, J = 8.1Hz), 7.41-7.45 (3H, m), 7.70-7.75 (1H, m), 8.16-8.19 (2H, m), 8.52-8.53 (4H, m), 10.48 (1H, s).
1H-NMR Spectrum (CDCl3)δ(ppm): 1.43(9H,s), 1.94-2.03(1H,m), 2.18-2.25(1H,m), 2.28(6H,s), 2.41-2.55(2H,m), 2.59(2H,t,J=5.8Hz), 4.23-4.26(2H,m), 4.34-4.36(1H,m), 5.12(2H,s), 5.16-5.18(1H,m), 7.32-7.38(5H,m).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.43 (9H, s), 1.94-2.03 (1H, m), 2.18-2.25 (1H, m), 2.28 (6H, s), 2.41-2.55 ( 2H, m), 2.59 (2H, t, J = 5.8Hz), 4.23-4.26 (2H, m), 4.34-4.36 (1H, m), 5.12 (2H, s), 5.16-5.18 (1H, m) , 7.32-7.38 (5H, m).
1H-NMR Spectrum (CDCl3)δ(ppm): 1.41(9H,s), 2.12-2.14 (2H,m), 2.20(6H,s), 2.46-2.60(4H,m), 4.08-4.13(3H,m), 4.31-4.37(2H,m), 5.31-5.36(3H,m), 6.37(1H,s), 6.78-6.81(1H,m), 6.87-6.90(1H,m), 7.21(1H,dd,J=4.8,7.9Hz), 7.30(2H,d,J=7.9Hz), 7.43(2H,d,J=8.2Hz), 7.56-7.61(1H,m), 7.98(1H,d,J=7.7Hz), 8.16-8.18(1H,m), 8.48(1H,dd,J=1.8,4.8Hz), 9.29(1H,brs).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.41 (9H, s), 2.12-2.14 (2H, m), 2.20 (6H, s), 2.46-2.60 (4H, m), 4.08-4.13 ( 3H, m), 4.31-4.37 (2H, m), 5.31-5.36 (3H, m), 6.37 (1H, s), 6.78-6.81 (1H, m), 6.87-6.90 (1H, m), 7.21 ( 1H, dd, J = 4.8,7.9Hz), 7.30 (2H, d, J = 7.9Hz), 7.43 (2H, d, J = 8.2Hz), 7.56-7.61 (1H, m), 7.98 (1H, d , J = 7.7Hz), 8.16-8.18 (1H, m), 8.48 (1H, dd, J = 1.8,4.8Hz), 9.29 (1H, brs).
1H-NMR Spectrum (DMSO-d6)δ(ppm): 1.24(3H,t,J=7.1Hz), 1.97-2.03(2H,m), 2.41-2.56(2H,m), 4.01-4.03(3H,m), 4.21(2H,q,J=7.1Hz), 5.32(2H,s), 6.66(1H,s), 6.84-6.86(1H,m), 6.98-7.01(1H,m), 7.30(2H,d,J=8.2Hz), 7.41(2H,d,J=8.1Hz), 7.43(1H,d,J=7.7Hz), 7.70-7.75(1H,m), 8.16-8.18(2H,m), 8.38(3H,brs), 8.52(1H,dd,J=1.8,4.8Hz), 10.48(1H,s).
1 H-NMR Spectrum (DMSO-d 6 ) δ (ppm): 1.24 (3H, t, J = 7.1 Hz), 1.97-2.03 (2H, m), 2.41-2.56 (2H, m), 4.01-4.03 ( 3H, m), 4.21 (2H, q, J = 7.1Hz), 5.32 (2H, s), 6.66 (1H, s), 6.84-6.86 (1H, m), 6.98-7.01 (1H, m), 7.30 (2H, d, J = 8.2Hz), 7.41 (2H, d, J = 8.1Hz), 7.43 (1H, d, J = 7.7Hz), 7.70-7.75 (1H, m), 8.16-8.18 (2H, m), 8.38 (3H, brs), 8.52 (1H, dd, J = 1.8,4.8Hz), 10.48 (1H, s).
1H-NMR Spectrum (CDCl3)δ(ppm): 1.27(3H,t,J=7.1Hz), 1.44(9H,s), 1.91-2.01(1H,m), 2.18-2.21(1H,m), 2.39-2.52(2H,m), 4.16-4.22(2H,m), 4.32-4.33(1H,m), 5.10-5.12(3H,m), 7.31-7.39(5H,m).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.27 (3H, t, J = 7.1Hz), 1.44 (9H, s), 1.91-2.01 (1H, m), 2.18-2.21 (1H, m) , 2.39-2.52 (2H, m), 4.16-4.22 (2H, m), 4.32-4.33 (1H, m), 5.10-5.12 (3H, m), 7.31-7.39 (5H, m).
1H-NMR Spectrum (CDCl3)δ(ppm): 1.27(3H,t,J=7.1Hz), 1.42(9H,s), 1.94-2.05(1H,m), 2.23-2.31(1H,m), 2.64-2.72(2H,m), 4.08(2H,s), 4.19(2H,q,J=7.1Hz), 4.33-4.34(1H,m), 5.33-5.36(3H,m), 6.33(1H,s), 6.79-6.81(1H,m), 6.87-6.90(1H,m), 7.18(1H,dd,J=4.9,7.8Hz), 7.30(2H,d,J=8.1Hz), 7.44(2H,d,J=8.2Hz), 7.56-7.61(1H,m), 7.92-7.95(1H,m), 8.17(1H,ddd,J=0.7,2.0,5.1Hz), 8.47(1H,dd,J=1.8,4.8Hz), 8.51(1H,brs).
1 H-NMR Spectrum (CDCl 3 ) δ (ppm): 1.27 (3H, t, J = 7.1Hz), 1.42 (9H, s), 1.94-2.05 (1H, m), 2.23-2.31 (1H, m) , 2.64-2.72 (2H, m), 4.08 (2H, s), 4.19 (2H, q, J = 7.1Hz), 4.33-4.34 (1H, m), 5.33-5.36 (3H, m), 6.33 (1H , s), 6.79-6.81 (1H, m), 6.87-6.90 (1H, m), 7.18 (1H, dd, J = 4.9,7.8Hz), 7.30 (2H, d, J = 8.1Hz), 7.44 ( 2H, d, J = 8.2Hz), 7.56-7.61 (1H, m), 7.92-7.95 (1H, m), 8.17 (1H, ddd, J = 0.7,2.0,5.1Hz), 8.47 (1H, dd, J = 1.8,4.8Hz), 8.51 (1H, brs).
親化合物である参考例1に記載の3-(3-(4-(ピリジン-2-イルオキシメチル)-ベンジル)-イソキサゾール-5-イル)-ピリジン-2-イルアミンと実施例1ないし3の化合物を、25℃において、Britton-Robinson緩衝液(イオン強度0.3)への溶解度と溶液中安定性を比較した。表1はその結果を示す。 [Comparative test of solubility in water]
3- (3- (4- (Pyridin-2-yloxymethyl) -benzyl) -isoxazol-5-yl) -pyridin-2-ylamine described in Reference Example 1, which is the parent compound, and Examples 1 to 3 The compounds were compared for solubility in solution and stability in solution at 25 ° C. in Britton-Robinson buffer (ionic strength 0.3). Table 1 shows the results.
1.実施例1の化合物のマウスにおける薬物動態評価
(1).投与液の調製
実施例1の化合物は、10mM塩酸溶液(和光純薬工業)を含む5%グルコース(大塚製薬)にて0.3mg/mLに溶解し、親化合物である活性体は3mM塩酸溶液(和光純薬工業)を含む5%グルコース(大塚製薬)にて0.3mg/mLに溶解した。 [Pharmacokinetic evaluation in mice]
1. Pharmacokinetic evaluation of the compound of Example 1 in mice
(1). Preparation of Administration Solution The compound of Example 1 was dissolved in 0.3 mg / mL in 5% glucose (Otsuka Pharmaceutical) containing 10 mM hydrochloric acid solution (Wako Pure Chemical Industries), and the active substance as the parent compound was It was dissolved in 0.3 mg / mL with 5% glucose (Otsuka Pharmaceutical) containing 3 mM hydrochloric acid solution (Wako Pure Chemical Industries).
5週齢の雌性ICR系マウス(日本チャールス・リバー)を使用し、実施例1の化合物は2匹を1群とし、活性体は3匹を1群とし、実施例1の化合物及び活性体を3mg/kgの投与量で尾静脈内へ投与した。実施例1の化合物は投与後30分、1、3、5、8時間に、活性体は投与後5分、15分、30分、1、2、4、6、8時間に尾静脈に穿刺し出血させ、ヘパリン処理したピペットで血液を採取した.採取した血液はサンプリングチューブに入れ氷冷下保存後、4℃、10,500xgで5分間遠心分離した。得られた血漿を正確に10μL採取し、分析時まで-20℃で保存した。 (2). Administration, Blood Collection and Plasma Collection Using a 5-week-old female ICR mouse (Nippon Charles River), the compound of Example 1 consists of 2 animals in 1 group and the active substance in 3 groups. The compound of Example 1 and the active form were administered into the tail vein at a dose of 3 mg / kg. The compound of Example 1 is punctured into the tail vein at 30 minutes, 1, 3, 5, 8 hours after administration, and the active substance is punctured at 5 minutes, 15 minutes, 30 minutes, 1, 2, 4, 6, 8 hours after administration. The blood was collected with a heparinized pipette. The collected blood was placed in a sampling tube and stored under ice cooling, and then centrifuged at 4 ° C. and 10,500 × g for 5 minutes. Accurate 10 μL of the obtained plasma was collected and stored at −20 ° C. until analysis.
実施例1の化合物及び活性体の血漿中濃度は液体クロマトグラフ質量分析計(LC-MS/MS:Waters, Quattro Ultima Pt)を用いて測定し、内部標準法にて定量した。イミプラミン塩酸塩(SIGMA)を、濃度が0.1μmol/Lになるようにアセトニトリル及びメタノール(1:1)混合溶液に溶解し、内部標準物質溶液(IS溶液)を調製した。血漿を融解後、氷上で冷却したままIS溶液を100μL加えて混合し、4℃、7800xgで10分間遠心分離(除蛋白)した後、上清をメンブレンフィルター(Millipore: MultiScreenTM)にて遠心ろ過し、濾液をLC-MS/MS(Waters:Quattro Ultima Pt)にて分析した。得られたクロマトグラムにおいて、実施例1の化合物、活性体化合物(実施例1化合物の親化合物)及び内部標準物質に対応するピークの面積を、解析ソフトウェア(Waters:MassLynx 4.0)で解析し、内部標準法にて、血漿中に含まれる化合物の濃度を算出した。実施例1の化合物を投与した後の活性体濃度は、分子量比、すなわち(実施例1の化合物分子量)/(活性体分子量)の値で補正した。 (3). Plasma concentration measurement method The plasma concentration of the compound and active substance of Example 1 was measured using a liquid chromatograph mass spectrometer (LC-MS / MS: Waters, Quattro Ultima Pt), and the internal standard method was used. Was quantified. Imipramine hydrochloride (SIGMA) was dissolved in a mixed solution of acetonitrile and methanol (1: 1) to a concentration of 0.1 μmol / L to prepare an internal standard substance solution (IS solution). After thawing plasma, add 100 μL of IS solution while cooling on ice, mix, centrifuge (protein removal) at 7800 xg for 10 minutes at 4 ° C, and then centrifuge the supernatant with a membrane filter (Millipore: MultiScreen TM ) The filtrate was analyzed by LC-MS / MS (Waters: Quattro Ultima Pt). In the obtained chromatogram, the areas of peaks corresponding to the compound of Example 1, the active compound (parent compound of Example 1 compound) and the internal standard substance were analyzed with analysis software (Waters: MassLynx 4.0), and the internal The concentration of the compound contained in plasma was calculated by a standard method. The active substance concentration after administration of the compound of Example 1 was corrected by the molecular weight ratio, that is, the value of (Compound molecular weight of Example 1) / (Active substance molecular weight).
(1).投与液の調製
実施例2及び3の化合物は、10mM塩酸溶液(和光純薬工業)を含む5%グルコース(大塚製薬)にてそれぞれ1、1.5mg/mLに溶解し、活性体は10mM塩酸溶液(和光純薬工業)を含む5%グルコース(大塚製薬)にて0.5mg/mLに溶解した。 2. Pharmacokinetic evaluation of the compounds of Examples 2 and 3 in mice
(1). Preparation of Dosing Solution The compounds of Examples 2 and 3 were dissolved in 1 and 1.5 mg / mL in 5% glucose (Otsuka Pharmaceutical) containing 10 mM hydrochloric acid solution (Wako Pure Chemical Industries), respectively. Was dissolved in 0.5 mg / mL with 5% glucose (Otsuka Pharmaceutical) containing 10 mM hydrochloric acid solution (Wako Pure Chemical Industries).
7週齢の雌性ICR系マウス(日本チャールス・リバー)を使用し、2匹を1群として、本発明化合物及び活性体をそれぞれ活性体当量換算して3mg/kgの投与量で尾静脈内へ投与した。投与後20分、45分、1.5、3、5、8時間に尾静脈に穿刺し出血させ、ヘパリン処理したピペットで血液を採取した。採取した血液はサンプリングチューブに入れ氷冷下保存後、4℃、10,500xgで5分間遠心分離した。得られた血漿を正確に5μL採取し、分析時まで-20℃で保存した。 (2). Administration, Blood Collection and Plasma Collection Using 7-week-old female ICR mice (Nippon Charles River), 2 mice as 1 group, the compound of the present invention and the active substance are each converted to active equivalents of 3 mg It was administered into the tail vein at a dose of / kg. At 20 minutes, 45 minutes, 1.5, 3, 5, and 8 hours after administration, the tail vein was punctured and bled, and blood was collected with a heparinized pipette. The collected blood was placed in a sampling tube and stored under ice cooling, and then centrifuged at 4 ° C. and 10,500 × g for 5 minutes. Accurate 5 μL of the obtained plasma was collected and stored at −20 ° C. until analysis.
実施例2、3の化合物及び活性体の血漿中濃度は液体クロマトグラフ質量分析計(LC-MS:Waters;ZQ mass detector)を用いて測定し、内部標準法にて定量した。イミプラミン塩酸塩(SIGMA)を、濃度が1μmol/Lになるようにアセトニトリルとメタノールとの混合溶液(9:1)に溶解し、内部標準物質溶液(IS溶液)を調製した。血漿を融解後、氷上で冷却したままIS溶液を50μL加えて混合し、4℃、1607xgで10分間遠心分離(除蛋白)し、上清をLC-MS(Waters:ZQ mass detector)にて分析した。得られたクロマトグラムにおいて、実施例2、3の化合物、活性体化合物及び内部標準物質に対応するピークの面積を、解析ソフトウェア(Waters:MassLynx 4.0)で解析し、内部標準法にて、血漿中に含まれる化合物の濃度を算出した。 (3). Method for measuring plasma concentration Plasma concentrations of the compounds and active substances of Examples 2 and 3 were measured using a liquid chromatograph mass spectrometer (LC-MS: Waters; ZQ mass detector), and an internal standard method was used. Was quantified. Imipramine hydrochloride (SIGMA) was dissolved in a mixed solution (9: 1) of acetonitrile and methanol so as to have a concentration of 1 μmol / L to prepare an internal standard substance solution (IS solution). After thawing plasma, add 50 μL of IS solution while cooling on ice, mix, centrifuge at 4 ° C and 1607 xg for 10 minutes (protein removal), and analyze supernatant with LC-MS (Waters: ZQ mass detector) did. In the obtained chromatogram, the areas of peaks corresponding to the compounds of Examples 2 and 3, the active compound, and the internal standard substance were analyzed with analysis software (Waters: MassLynx 4.0). The concentration of the compound contained in was calculated.
Claims (18)
- 下式(I)で表される化合物又はその塩;
R1が、水素原子、ハロゲン原子、アミノ基、R11-NH-(R11が、C1-6アルキル基、ヒドロキシC1-6アルキル基、C1-6アルコキシC1-6アルキル基、又はC1-6アルコキシカルボニルC1-6アルキル基を意味する。)、R12-(CO)-NH-(R12が、C1-6アルキル基又はC1-6アルコキシC1-6アルキル基)、C1-6アルキル基、ヒドロキシC1-6アルキル基、シアノC1-6アルキル基、C1-6アルコキシ基、又はC1-6アルコキシC1-6アルキル基を意味し;
R2が式
X及びYの一方が、窒素原子を、他方が、窒素原子又は酸素原子を意味し;
環Aが、ハロゲン原子若しくはC1-6アルキル基を1個若しくは2個有していてもよい、5若しくは6員のへテロアリール環又はベンゼン環を意味し;
Zが、単結合、メチレン基、エチレン基、酸素原子、硫黄原子、-CH2O-、-OCH2-、-NH-、-CH2NH-、-NHCH2-、-CH2S-、又は-SCH2-を意味し;
R3が、水素原子、ハロゲン原子、又は、それぞれ置換基群αから選ばれる置換基を1個若しくは2個有していてもよい、C1-6アルキル基、C3-8シクロアルキル基、C6-10アリール基、5若しくは6員へテロアリール基、又は5若しくは6員の非芳香族系へテロ環式基を意味し;
R4が、水素原子又はハロゲン原子を意味し;
Rが、水素原子、又はジメチルアミノ基で置換されていてもよいC1-6アルキル基を意味する。
[置換基群α]
ハロゲン原子、シアノ基、C1-6アルキル基、C1-6アルコキシ基、C1-6アルコキシカルボニル基、C3-8シクロアルキル基、C2-6アルケニル基、及びC2-6アルキニル基。 A compound represented by the following formula (I) or a salt thereof;
R 1 is a hydrogen atom, a halogen atom, an amino group, R 11 —NH— (R 11 is a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a C 1-6 alkoxy C 1-6 alkyl group, Or a C 1-6 alkoxycarbonyl C 1-6 alkyl group), R 12 — (CO) —NH— (wherein R 12 represents a C 1-6 alkyl group or a C 1-6 alkoxy C 1-6 alkyl group). Group), a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, a cyano C 1-6 alkyl group, a C 1-6 alkoxy group, or a C 1-6 alkoxy C 1-6 alkyl group;
R 2 is the formula
One of X and Y means a nitrogen atom, and the other means a nitrogen atom or an oxygen atom;
Ring A represents a 5- or 6-membered heteroaryl ring or benzene ring optionally having one or two halogen atoms or C 1-6 alkyl groups;
Z is a single bond, a methylene group, an ethylene group, an oxygen atom, a sulfur atom, -CH 2 O -, - OCH 2 -, - NH -, - CH 2 NH -, - NHCH 2 -, - CH 2 S-, Or -SCH 2- ;
R 3 may have a hydrogen atom, a halogen atom, or one or two substituents each selected from substituent group α, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, Means a C 6-10 aryl group, a 5 or 6 membered heteroaryl group, or a 5 or 6 membered non-aromatic heterocyclic group;
R 4 represents a hydrogen atom or a halogen atom;
R represents a hydrogen atom or a C 1-6 alkyl group which may be substituted with a dimethylamino group.
[Substituent group α]
Halogen atom, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkoxycarbonyl group, C 3-8 cycloalkyl group, C 2-6 alkenyl group, and C 2-6 alkynyl group . - X及びYの一方が窒素原子で、他方が酸素原子である請求項1に記載の化合物又はその塩。 The compound or a salt thereof according to claim 1, wherein one of X and Y is a nitrogen atom and the other is an oxygen atom.
- X及びYがともに窒素原子である請求項1に記載の化合物又はその塩。 The compound or salt thereof according to claim 1, wherein X and Y are both nitrogen atoms.
-
- Rが水素原子、メチル基、エチル基、又は2-ジメチルアミノエチル基である請求項1ないし6のいずれか1項に記載の化合物又はその塩。 7. The compound or a salt thereof according to any one of claims 1 to 6, wherein R is a hydrogen atom, a methyl group, an ethyl group, or a 2-dimethylaminoethyl group.
- R1が、水素原子、アミノ基、又はC1-6アルコキシC1-6アルキル基である請求項7に記載の化合物又はその塩。 The compound or a salt thereof according to claim 7, wherein R 1 is a hydrogen atom, an amino group, or a C 1-6 alkoxy C 1-6 alkyl group.
- R1がアミノ基であって、Rが水素原子、メチル基、エチル基、又は2-ジメチルアミノエチル基である請求項1ないし6のいずれか1項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 6, wherein R 1 is an amino group, and R is a hydrogen atom, a methyl group, an ethyl group, or a 2-dimethylaminoethyl group.
- R1がアミノ基であって、Rがメチル基、エチル基、又は2-ジメチルアミノエチル基である請求項1ないし6のいずれか1項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 6, wherein R 1 is an amino group, and R is a methyl group, an ethyl group, or a 2-dimethylaminoethyl group.
- 環Aが、ピリジン環、ベンゼン環、フラン環、チオフェン環、又はピロール環である請求項1ないし10のいずれか1項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 10, wherein Ring A is a pyridine ring, a benzene ring, a furan ring, a thiophene ring, or a pyrrole ring.
- 環Aが、ピリジン環又はベンゼン環である請求項11に記載の化合物又はその塩。 The ring or a salt thereof according to claim 11, wherein ring A is a pyridine ring or a benzene ring.
- Zが、酸素原子、-CH2O-、又は-OCH2-である請求項1ないし12のいずれか1項に記載の化合物又はその塩。 The compound or a salt thereof according to any one of claims 1 to 12, wherein Z is an oxygen atom, -CH 2 O-, or -OCH 2- .
- 請求項1ないし13のいずれか1項に記載の化合物又はその塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a salt thereof.
- 請求項1ないし13のいずれか1項に記載の化合物又はその塩を含有する医薬。 A medicament comprising the compound or salt thereof according to any one of claims 1 to 13.
- 請求項1ないし13のいずれか1項に記載の化合物を有効成分とする抗真菌剤。 An antifungal agent comprising the compound according to any one of claims 1 to 13 as an active ingredient.
- 請求項1ないし13のいずれか1項に記載の化合物又はその塩の薬理学的有効量を投与して、真菌感染症を予防及び/又は治療する方法。 A method for preventing and / or treating a fungal infection by administering a pharmacologically effective amount of the compound or salt thereof according to any one of claims 1 to 13.
- 抗真菌剤の製造のための請求項1ないし13のいずれか1項に記載の化合物又はその塩の使用。 Use of the compound or a salt thereof according to any one of claims 1 to 13 for the manufacture of an antifungal agent.
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RU2011116160/04A RU2011116160A (en) | 2008-10-24 | 2009-10-22 | Pyridine derivatives substituted with a heterocyclic ring and y-glutamylamino group and containing antifungal agents |
JP2010534715A JPWO2010047120A1 (en) | 2008-10-24 | 2009-10-22 | Pyridine derivatives substituted with heterocycles and γ-glutamylamino groups and antifungal agents containing them |
EP09821820A EP2351752A4 (en) | 2008-10-24 | 2009-10-22 | PYRIDINE DERIVATIVE HAVING SUBSTITUTED HETERO RING AND SUBSTITUTED y-GLUTAMYLAMINO GROUP, AND ANTI-FUNGAL AGENT COMPRISING SAME |
NZ592416A NZ592416A (en) | 2008-10-24 | 2009-10-22 | PYRIDINE DERIVATIVE HAVING SUBSTITUTED HETERO RING AND SUBSTITUTED y-GLUTAMYLAMINO GROUP, AND ANTI-FUNGAL AGENT COMPRISING SAME |
BRPI0920614A BRPI0920614A2 (en) | 2008-10-24 | 2009-10-22 | heterocyclic ring-substituted pyridine derivatives and <sym> -glutamylamino group, and antifungal agents containing these derivatives |
CA2740982A CA2740982A1 (en) | 2008-10-24 | 2009-10-22 | Pyridine derivatives substituted with heterocyclic ring and y-glutamylamino group, and antifungal agents containing same |
MX2011003389A MX2011003389A (en) | 2008-10-24 | 2009-10-22 | Pyridine derivative having substituted hetero ring and substituted î³-glutamylamino group, and anti-fungal agent comprising same. |
CN2009801414232A CN102186846A (en) | 2008-10-24 | 2009-10-22 | Pyridine derivative having substituted hetero ring and substituted -glutamylamino group, and anti-fungal agent comprising same |
AU2009307574A AU2009307574A1 (en) | 2008-10-24 | 2009-10-22 | Pyridine derivatives substituted with heterocyclic ring and gamma-glutamylamino group, and anti-fungal agents containing same |
IL211980A IL211980A0 (en) | 2008-10-24 | 2011-03-28 | Pyridine derivative having substituted hetero ring and substituted ??-glutamylamino group, and anti-fungal agent comprising same |
ZA2011/02840A ZA201102840B (en) | 2008-10-24 | 2011-04-15 | PYRIDINE DERIVATIVES SUBSTITUTED WITH HETEROCYCLIC RING AND y-GLUTAMYLAMINO GROUP,AND ANTIFUNGAL AGENTS CONTAINING SAME |
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WO2011051198A2 (en) | 2009-10-30 | 2011-05-05 | Bayer Cropscience Ag | Pyridine derivatives as agricultural pesticides |
EP2345328A1 (en) * | 2008-09-19 | 2011-07-20 | Sumitomo Chemical Company, Limited | Composition for agricultural use |
JP2021530445A (en) * | 2018-06-25 | 2021-11-11 | アンプリックス ファーマシューティカルズ,インク. | Pyridine derivatives substituted with heterocycles and amino groups |
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- 2009-10-22 KR KR1020117009091A patent/KR20110069823A/en not_active Application Discontinuation
- 2009-10-22 JP JP2010534715A patent/JPWO2010047120A1/en not_active Withdrawn
- 2009-10-22 CN CN2009801414232A patent/CN102186846A/en active Pending
- 2009-10-22 TW TW098135851A patent/TW201018676A/en unknown
- 2009-10-22 PE PE2011000914A patent/PE20120024A1/en not_active Application Discontinuation
- 2009-10-22 EP EP09821820A patent/EP2351752A4/en not_active Withdrawn
- 2009-10-22 BR BRPI0920614A patent/BRPI0920614A2/en not_active IP Right Cessation
- 2009-10-22 RU RU2011116160/04A patent/RU2011116160A/en not_active Application Discontinuation
- 2009-10-22 AU AU2009307574A patent/AU2009307574A1/en not_active Abandoned
- 2009-10-22 MX MX2011003389A patent/MX2011003389A/en not_active Application Discontinuation
- 2009-10-22 WO PCT/JP2009/005559 patent/WO2010047120A1/en active Application Filing
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EP2345328A1 (en) * | 2008-09-19 | 2011-07-20 | Sumitomo Chemical Company, Limited | Composition for agricultural use |
EP2345328A4 (en) * | 2008-09-19 | 2014-06-25 | Sumitomo Chemical Co | Composition for agricultural use |
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JP2021530445A (en) * | 2018-06-25 | 2021-11-11 | アンプリックス ファーマシューティカルズ,インク. | Pyridine derivatives substituted with heterocycles and amino groups |
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US8188119B2 (en) | 2012-05-29 |
MX2011003389A (en) | 2011-04-21 |
TW201018676A (en) | 2010-05-16 |
KR20110069823A (en) | 2011-06-23 |
PE20120024A1 (en) | 2012-02-22 |
BRPI0920614A2 (en) | 2015-12-22 |
US20100105737A1 (en) | 2010-04-29 |
IL211980A0 (en) | 2011-06-30 |
EP2351752A4 (en) | 2012-05-30 |
RU2011116160A (en) | 2012-11-27 |
ZA201102840B (en) | 2011-12-28 |
NZ592416A (en) | 2011-12-22 |
EP2351752A1 (en) | 2011-08-03 |
JPWO2010047120A1 (en) | 2012-03-22 |
CN102186846A (en) | 2011-09-14 |
CA2740982A1 (en) | 2010-04-29 |
US20120277439A1 (en) | 2012-11-01 |
AU2009307574A1 (en) | 2010-04-29 |
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